Aryl-isoxazolo-4-yl-oxadiazole derivatives

ABSTRACT

The present invention is concerned with isoxazol-4-yl-oxadiazole derivatives of formula 
                         
wherein
     R 1 ,   R 2 , and   R 3 , are as defined in the specification and pharmaceutically acceptable acid addition salts thereof.   

     This class of compounds has high affinity and selectivity for GABA A α5 receptor binding sites and might be useful as cognitive enhancer or for the treatment of cognitive disorders like Alzheimer&#39;s disease.

PRIORITY TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 11/639,695,filed Dec. 15, 2006, now pending; which claims the benefit of EuropeanApplication No. 05112956.7, filed Dec. 23, 2005. The entire contents ofthe above-identified applications are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Receptors for the major inhibitory neurotransmitter, gamma-aminobutyricacid (GABA), are divided into two main classes: (1) GABA A receptors,which are members of the ligand-gated ion channel superfamily and (2)GABA B receptors, which are members of the G-protein linked receptorfamily. The GABA A receptor complex which is a membrane-boundheteropentameric protein polymer is composed principally of α, β and γsubunits.

Presently a total number of 21 subunits of the GABA A receptor have beencloned and sequenced. Three types of subunits (α, β and γ) are requiredfor the construction of recombinant GABA A receptors which most closelymimic the biochemical, electrophysiological and pharmacologicalfunctions of native GABA A receptors obtained from mammalian braincells. There is strong evidence that the benzodiazepine binding sitelies between the α and γ subunits. Among the recombinant GABA Areceptors, α1β2γ2 mimics many effects of the classical type-I BzRsubtypes, whereas α2β2γ2, α3β2γ2 and α5β2γ2 ion channels are termedtype-II BzR. It has been shown by McNamara and Skelton in Psychobiology,21:101-108 that the benzodiazepine receptor inverse agonist β-CCMenhance spatial learning in the Morris watermaze. However, β-CCM andother conventional benzodiazepine receptor inverse agonists areproconvulsant or convulsant which prevents their use as cognitionenhancing agents in humans. In addition, these compounds arenon-selective within the GABA A receptor subunits, whereas a GABA A α5receptor partial or full inverse agonist which is relatively free ofactivity at GABA A α1 and/or α2 and/or α3 receptor binding sites can beused to provide a medicament which is useful for enhancing cognitionwith reduced or without proconvulsant activity. It is also possible touse GABA A α5 inverse agonists which are not free of activity at GABA Aα1 and/or α2 and/or α3 receptor binding sites but which are functionallyselective for α5 containing subunits. However, inverse agonists whichare selective for GABA A α5 subunits and are relatively free of activityat GABA A α1, α2 and α3 receptor binding sites are preferred.

SUMMARY OF THE INVENTION

The present invention provides isoxazol-4-yl-oxadiazole derivatives offormula I

wherein

-   R¹ is hydrogen, halogen, aryl, heterocyclyl, heteroaryl, cyano,    lower alkyl, —(CH₂)_(n)-cycloalkyl, —(CH₂)_(n)—N(R)₂,    —(CH₂)_(n)—O-lower alkyl or —(CH₂)_(n)—OH;-   n is 0, 1 or 2-   R is hydrogen or lower alkyl;-   R² is cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is    optionally substituted by one or more substituents selected from the    group consisting of halogen, cyano, nitro, lower alkyl, lower    alkoxy, lower alkoxy substituted by halogen, lower alkyl substituted    by halogen, C(O)O-lower alkyl, lower alkylsulfonyl, —NR^(a)R^(b),    -   —C(O)—NR^(a)R^(b), —C(O)-heterocyclyl, benzyloxy, heterocyclyl        optionally substituted by hydroxy, halogen or lower alkyl, and        heteroaryl optionally substituted by lower alkyl;        -   R^(a) and R^(b) are each independently hydrogen, lower            alkylsulfonyl, —C(O)H, —(CH₂)_(n)—N(R)₂, —(CH₂)_(n)—O-lower            alkyl, —(CH₂)_(n)—S-lower alkyl, —(CH₂)_(n)—S(O)₂-lower            alkyl, heteroarylsulfonyl, lower alkyl,            —(CH₂)_(n)-heterocyclyl optionally substituted by lower            alkyl, —(CH₂)_(n)-cycloalkyl, —(CH₂)_(n)-heteroaryl,            —(CH₂)_(n)—OH, or —(CO)—R′, wherein R′ is lower alkyl,            cycloalkyl or heteroaryl;-   R³ is aryl or heteroaryl, each of which is optionally substituted by    halogen or lower alkyl substituted by halogen;    and pharmaceutically acceptable acid addition salts thereof.

The present invention also provides pharmaceutical compositionscontaining a therapeutically effective amount of a compound of formula Ior a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier. The invention further provides processes forpreparation of the compounds of the invention and pharmaceuticalcompositions containing them.

This class of compounds has high affinity and selectivity for GABA A α5receptor binding sites and might be useful as a cognitive enhancer orfor the treatment of cognitive disorders like Alzheimer's disease.Therefor, the present invention provides a methods for enhancingcognition or treating cognitive disorders which comprise administeringto an individual, a therapeutically effective amount of a compound offormula I or a pharmaceutically acceptable salt thereof.

The most preferred indication in accordance with the present inventionis Alzheimer's disease.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of the general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination. It must be noted that, as used in thespecification and the appended claims, the singular forms “a”, “an,” and“the” include plural forms unless the context clearly dictatesotherwise.

As used herein, the term “lower alkyl” denotes a straight- orbranched-chain hydrocarbon group containing from 1-7, preferably from1-4, carbon atoms, for example, methyl, ethyl, propyl, isopropyl,n-butyl, i-butyl, t-butyl and the like.

The term “lower alkoxy” denotes a lower alkyl group as definedhereinabove linked via an oxygen atom. Examples of lower alkoxy includemethoxy and ethoxy as well as those groups that are specificallyillustrated with the examples of the compounds of the inventionhereinafter.

The terms “lower alkyl substituted by halogen” and “lower alkoxysubstituted by halogen” respectively denote a lower alkyl or loweralkoxy group as defined hereinabove, in which one or more of thehydrogen atoms have be replaced by a halogen atom; i.e., the lower alkylor lower alkoxy group substituted by one or more halogen atom;preferably by one, two or three fluorine atoms. Examples of such groupsinclude OCHF₂, OCF₃, and CF₃, as well as those groups that arespecifically illustrated with the examples of the compounds of theinvention hereinafter.

The term “lower alkylsulfonyl” denotes a lower alkyl group as definedhereinabove linked via an —S(O)₂— group. Examples of lower alkylsulfonylgroups include methylsulfonyl and ethylsulfonyl as well as those groupsthat are specifically illustrated with the examples of the compounds ofthe invention hereinafter.

The term “heterocyclyl” denotes a monocyclic or bicyclic ring comprisingfrom 1 to 9 carbon atoms as ring members, with the remaining ring memberatoms being selected from one or more O, N and S. Preferred heterocyclylgroups are 5 or 6 membered heterocycloalkyl groups. Examples of suchgroups include piperidine, piperazine, morpholine, pyrrolidin,pyrrolidin-2-one, imidazolidin-2-one, tetrahydrofuran, thiomorpholine,thiomorpholine-1-oxide, thiomorpholinel-1,1-dioxide, 1-H-benzoimidazole,1,3-dihydro-benzolimidazole-2-one, tetrahydro-pyrane, and1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one as well as those groupsspecifically illustrated by the examples herein below.

The term “aryl” denotes an unsaturated, aromatic carbon ring, forexample a phenyl, benzyl or naphthyl group. A preferred aryl group isphenyl.

The term “halogen” denotes chlorine, iodine, fluorine and bromine.

The term “cycloalkyl” denotes a cyclic hydrocarbon ring, having from 3to 7 carbon ring atoms, for example, cyclopropyl, cyclopentyl orcyclohexyl.

The term “heteroaryl” denotes a ring system containing one or two rings,wherein at least one ring is aromatic in nature and contains from one tothree heteroatoms, such as N, O or S atoms. Examples of such heteroarylgroups include quinolyl, indolyl, pyridinyl, triazolyl, benzotriazolyl,isoxazolyl, furanyl, thiophenyl, benzoimidazolyl,dihydrobenzimidazolyl-2-one, imidazolyl, oxazolyl, oxadiazolyl andpyrazinyl as well as those groups specifically illustrated by theexamples herein below.

The term “heteroarylsulfonyl” denotes a heteroaryl group as definedabove which is attached via a sulfonyl group.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The term “pharmaceutically acceptable acid addition salts” embracessalts with inorganic and organic acids, such as hydrochloric acid,nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid,fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid,methane-sulfonic acid, p-toluenesulfonic acid and the like.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

The present invention provides isoxazol-4-yl-oxadiazole derivatives offormula I

wherein

-   R¹ is hydrogen, halogen, aryl, heterocyclyl, heteroaryl, cyano,    lower alkyl, —(CH₂)_(n)-cycloalkyl, —(CH₂)_(n)—N(R)₂,    —(CH₂)_(n)—O-lower alkyl or —(CH₂)_(n)—OH;-   n is 0, 1 or 2-   R is hydrogen or lower alkyl;-   R² is cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is    optionally substituted by one or more substituents selected from the    group consisting of halogen, cyano, nitro, lower alkyl, lower    alkoxy, lower alkoxy substituted by halogen, lower alkyl substituted    by halogen, C(O)O-lower alkyl, lower alkylsulfonyl, —NR^(a)R^(b),    -   —C(O)—NR^(a)R^(b), —C(O)-heterocyclyl, benzyloxy, heterocyclyl        optionally substituted by hydroxy, halogen or lower alkyl, and        heteroaryl optionally substituted by lower alkyl;        -   R^(a) and R^(b) are each independently hydrogen, lower            alkylsulfonyl, —C(O)H, —(CH₂)_(n)—N(R)₂, —(CH₂)_(n)—O-lower            alkyl, —(CH₂)_(n)—S-lower alkyl, —(CH₂)_(n)—S(O)₂-lower            alkyl, heteroarylsulfonyl, lower alkyl,            —(CH₂)_(n)-heterocyclyl optionally substituted by lower            alkyl, —(CH₂)_(n)-cycloalkyl, —(CH₂)_(n)-heteroaryl,            —(CH₂)_(n)—OH, or —(CO)—R′, wherein R′ is lower alkyl,            cycloalkyl or heteroaryl;-   R³ is aryl or heteroaryl, each of which is optionally substituted by    halogen or lower alkyl substituted by halogen;    and pharmaceutically acceptable acid addition salts thereof.

Preferred are compounds that have a binding activity (hKi) of lower than400 nM, are selective for GABA A α5 subunits, and are relatively free ofactivity at GABA A α1, α2 and α3 receptor binding sites. Most preferredare compounds which have a binding activity (hKi) of lower than 35 nM atthe GABA A α5 subunit.

In a certain embodiment, the compounds of the invention are thosecompounds, wherein R² is aryl, which is optionally substituted by one ormore substituents selected from the group consisting of halogen, cyano,nitro, lower alkyl, lower alkoxy, lower alkoxy substituted by halogen,lower alkyl substituted by halogen, C(O)O-lower alkyl, loweralkylsulfonyl, —NR^(a)R^(b), —C(O)—NR^(a)R^(b), —C(O)-heterocyclyl,benzyloxy, heterocyclyl optionally substituted by hydroxy, halogen orlower alkyl, and heteroaryl optionally substituted by lower alkyl, andthe other definitions are as above.

The following are examples of such compounds:

-   2-(5-methyl-3-phenyl-isoxazol-4-yl)-5-phenyl-[1,3,4]oxadiazole,-   2-(5-methyl-3-phenyl-isoxazol-4-yl)-5-o-tolyl-[1,3,4]oxadiazole,-   2-(3-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   2-(2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   2-(4-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   2-(2-ethoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   2-(2,4-dimethoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   2-(2-methoxy-4-nitro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   2-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine,-   3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine,    2-(2-methoxy-4-methyl-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,    2-(2,5-dimethoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   cyclopropanecarboxylic acid    {3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amide,-   cyclopropanecarboxylic acid    {3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methyl-amide,-   (4-{5-[5-(2-cyclopropyl-ethyl)-3-phenyl-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-3-methoxy-phenyl)-cyclopropylmethyl-amine,-   cyclopropylmethyl-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amine,-   4-{5-[5-(2-cyclopropyl-ethyl)-3-phenyl-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-3-methoxy-phenylamine,-   N-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-bis-methanesulfonyl-amine,-   N-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methanesulfonamide,-   thiophene-3-carboxylic    acid-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amide,-   2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,    4-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine,-   4-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine    1,1-dioxide,-   1-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-piperidin-4-ol,-   2-(4-methanesulfonyl-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   2-(3-methanesulfonyl-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   5-(5-methyl-3-phenyl-isoxazol-4-yl)-2-(4-nitro-phenyl)-[1,3,4]oxadiazole,-   2-(4-imidazol-1-yl-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine,-   2-(4-fluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   4-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine,-   4-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine    1,1-dioxide,-   4-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine    1-oxide,-   (2S*,6R*)-2,6-dimethyl-4-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine,-   2-(2-difluoromethoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,    2-(5-methyl-3-phenyl-isoxazol-4-yl)-5-(2-trifluoromethoxy-phenyl)-[1,3,4]oxadiazole,    2-(3-fluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   2-(2-benzyloxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   1-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-piperidine,-   2-(2-methoxy-4-trifluoromethyl-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   2-(5-methyl-3-phenyl-isoxazol-4-yl)-5-(4-trifluoromethyl-phenyl)-[1,3,4]oxadiazole,-   2-(4-difluoromethoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,    4-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine    1-oxide,-   4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-benzonitrile,-   2-[2-methoxy-4-(2-methyl-imidazol-1-yl)-phenyl]-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   2-[4-(2-methyl-imidazol-1-yl)-phenyl]-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   2-(5-ethyl-3-phenyl-isoxazol-4-yl)-5-(4-fluoro-2-methoxy-phenyl)-[1,3,4]oxadiazole,-   2-(4-fluoro-2-methoxy-phenyl)-5-(5-isopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   thiophene-2-sulfonic acid    {3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amide,-   propane-2-sulfonic acid    {3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amide,-   {3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-(tetrahydro-pyran-4-yl)-amine,-   {3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-(1-methyl-piperidin-4-yl)-amine,-   1-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-piperazine,-   1-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-4-methyl-piperazine,-   4-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine,-   2-(5-cyclopropyl-3-phenyl-isoxazol-4-yl)-5-(2-methoxy-phenyl)-[1,3,4]oxadiazole,-   4-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-benzoic    acid methyl ester,-   {3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-dimethyl-amine,-   2-(5-cyclopropyl-3-phenyl-isoxazol-4-yl)-5-(4-fluoro-2-methoxy-phenyl)-[1,3,4]oxadiazole,-   2-(2,4-difluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   4-{4-[5-(5-cyclopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine,-   N-cyclopropyl-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-benzamide,-   N-cyclopropylmethyl-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-benzamide,-   {4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholin-4-yl-methanone,-   4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-N-(tetrahydro-pyran-4-yl)-benzamide,-   {4-[5-(5-cyclopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-(tetrahydro-pyran-4-yl)-amine,-   2-(2,5-difluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   2-(2,3-difluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   2-(2-methoxy-4-[1,2,3]triazol-2-yl-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   2-(2-methoxy-4-[1,2,3]triazol-1-yl-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   {4-[5-(4-fluoro-2-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-3-phenyl-isoxazol-5-ylmethyl}-methyl-amine,-   N-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-acetamide,-   N-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-propionamide,-   2-(4-fluoro-2-methoxy-phenyl)-5-(5-methoxymethyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole,-   {4-[5-(4-fluoro-2-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-3-phenyl-isoxazol-5-yl}-methanol,-   4-(4-{5-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-3-methoxy-phenyl)-morpholine,-   4-{3-methoxy-4-[5-(3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine,-   4-{4-[5-(3,5-diphenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine,-   4-(4-{5-[3-(2-chloro-phenyl)-5-methyl-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-3-methoxy-phenyl)-morpholine,-   4-(4-{5-[3-(4-fluoro-phenyl)-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-3-methoxy-phenyl)-morpholine,-   4-(4-{5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-3-methoxy-phenyl)-morpholine,-   4-{3-methoxy-4-[5-(5-methyl-3-pyridin-3-yl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine,-   4-(3-methoxy-4-{5-[5-methyl-3-(4-trifluoromethyl-phenyl)-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-phenyl)-morpholine,-   4-(3-methoxy-4-{5-[5-methyl-3-(4-methyl-phenyl)-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-phenyl)-morpholine,-   4-{4-[5-(5-chloro-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine,-   {4-[5-(2-methoxy-4-morpholin-4-yl-phenyl)-[1,3,4]oxadiazol-2-yl]-3-phenyl-isoxazol-5-yl}-dimethyl-amine,-   4-{4-[5-(2-methoxy-4-morpholin-4-yl-phenyl)-[1,3,4]oxadiazol-2-yl]-3-phenyl-isoxazol-5-yl}-morpholine,-   4-(4-{5-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-3-methoxy-phenyl)-morpholine,-   4-(4-{5-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-3-methoxy-phenyl)-morpholine,-   4-{3-methoxy-4-[5-(5-methyl-3-thiophen-2-yl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine,-   ethyl-{4-[5-(2-methoxy-4-morpholin-4-yl-phenyl)-[1,3,4]oxadiazol-2-yl]-3-phenyl-isoxazol-5-yl}-amine,-   4,4-difluoro-1-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-piperidine,-   4-{3-methoxy-4-[5-(3-phenyl-5-pyrazol-1-yl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine,-   4-{2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine,-   4-[5-(2-methoxy-4-morpholin-4-yl-phenyl)-[1,3,4]oxadiazol-2-yl]-3-phenyl-isoxazole-5-carbonitrile,-   4-{2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine,-   4-{2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine    1,1-dioxide,-   2-(5-methyl-3-phenyl-isoxazol-4-yl)-5-(2,4,5-trifluoro-phenyl)-[1,3,4]oxadiazole,-   4-{2,5-difluoro-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine,-   4-{2,5-difluoro-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine    1,1-dioxide,-   4-{3-methoxy-4-[5-(5-methyl-3-thiophen-3-yl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine,-   (2-methoxy-ethyl)-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amine,-   {2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-(2-methylsulfanyl-ethyl)-amine,-   {2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-(2-methanesulfonyl-ethyl)-amine,-   1-(2-{2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamino}-ethyl)-pyrrolidin-2-one,-   2-{2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamino}-ethanol,-   rac-{2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-(tetrahydro-furan-2-ylmethyl)-amine,-   {2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-pyridin-2-ylmethyl-amine,-   {2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-(2-pyrrolidin-1-yl-ethyl)-amine,-   1-(2-{2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamino}-ethyl)-imidazolidin-2-one,-   N-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-formamide    and-   N′-{2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-N,N-dimethyl-ethane-1,2-diamine.

In a certain embodiment, the compounds of the invention are thosecompounds, wherein R² is heteroaryl, which is optionally substituted byone or more substituents selected from the group consisting of halogen,cyano, nitro, lower alkyl, lower alkoxy, lower alkoxy substituted byhalogen, lower alkyl substituted by halogen, C(O)O-lower alkyl, loweralkylsulfonyl, —NR^(a)R^(b), —C(O)—NR^(a)R^(b), —C(O)-heterocyclyl,benzyloxy, heterocyclyl optionally substituted by hydroxy, halogen orlower alkyl, and heteroaryl optionally substituted by lower alkyl, andthe other definitions are as above, for example the following compounds

-   2-chloro-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   8-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-quinoline,-   2-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazole,-   5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dihydro-benzoimidazol-2-one,-   4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-quinoline,-   5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-ylamine,-   1,3-dimethyl-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dihydro-benzoimidazol-2-one,-   5-[5-(5-isopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one,-   2-chloro-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   4-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-morpholine,-   5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-indole,    2-methoxy-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   2-chloro-6-methoxy-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   2,6-dimethoxy-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   2-(5-Methyl-3-phenyl-isoxazol-4-yl)-5-thiophen-2-yl-[1,3,4]oxadiazole,-   2-(5-methyl-3-phenyl-isoxazol-4-yl)-5-thiophen-3-yl-[1,3,4]oxadiazole,-   4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazole,-   4-{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-morpholine,-   2-{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-ylamino}-ethanol,-   4-{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-thiomorpholine,-   {5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-(tetrahydro-pyran-4-yl)-amine,-   5′-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol,-   4-{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-thiomorpholine    1,1-dioxide and-   4-{6-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-3-yl}-morpholine.

In a certain embodiment, the compounds of the invention are thosecompounds, wherein R² is heterocyclyl, which is optionally substitutedby one or more substituents selected from the group consisting ofhalogen, cyano, nitro, lower alkyl, lower alkoxy, lower alkoxysubstituted by halogen, lower alkyl substituted by halogen, C(O)O-loweralkyl, lower alkylsulfonyl, —NR^(a)R^(b), —C(O)—NR^(a)R^(b),—C(O)-heterocyclyl, benzyloxy, heterocyclyl optionally substituted byhydroxy, halogen or lower alkyl, and heteroaryl optionally substitutedby lower alkyl, and the other definitions are as above.

In a certain embodiment, the compounds of the invention are thosecompounds, wherein R² is pyridinyl optionally substituted by halogen,lower alkoxy, heterocyclyl or NR^(a)R^(b), wherein R^(a) and R^(b) areas defined above, for example the following compounds:

-   2-chloro-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   2-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-ylamine,-   2-chloro-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   4-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-morpholine,-   2-methoxy-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   2-chloro-6-methoxy-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   2,6-dimethoxy-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   4-{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-morpholine,-   [5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-ylamino}-ethanol,-   4-{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-thiomorpholine,-   {5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-(tetrahydro-pyran-4-yl)-amine,-   5′-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol,-   4-{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-thiomorpholine-   1,1-dioxide and    4-{6-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-3-yl}-morpholine.

In a certain embodiment, the compounds of the invention are thosecompounds, wherein R² is quinolinyl, for example the followingcompounds:

-   8-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-quinoline    and-   4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-quinoline.

In a certain embodiment, the compounds of the invention are thosecompounds, wherein R² is 1-H-benzoimidazol-5-yl,1,3-dihydro-benzolimidazol-2-on-5-yl or1,3-dimethyl-1,3-dihydro-benzoimidazol-2-on-5-yl, for example thefollowing compounds:5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazole,

-   5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dihydro-benzoimidazol-2-one,-   1,3-dimethyl-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dihydro-benzoimidazol-2-one    and-   5-[5-(5-isopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one.

The present compounds of formula I and their pharmaceutically acceptablesalts can be prepared by methods known in the art, for example, byprocesses described below, which processes comprise

reacting a compound of formula II

with a compound of formula III

in the presence of phosphorous oxychlorideto give a compound of formula

wherein R¹, R² and R³ are as described above,and, if desired, converting a compound of formula I into apharmaceutically acceptable salt.

The following schemes describe the processes for preparation ofcompounds of formula I in more detail. All starting materials are knowncompounds or can be prepared according to methods known in the art.

R is halogen, cyano, lower alkyl, lower alkoxy, lower alkoxy substitutedby halogen, lower alkyl substituted by halogen, C(O)O-lower alkyl, loweralkylsulfonyl,

—C(O)—NR^(a)R^(b), —C(O)-heterocyclyl, benzyloxy, heterocyclyloptionally substituted by hydroxy, halogen or lower alkyl, or isheteroaryl optionally substituted by lower alkyl and the otherdefinitions are as above.

In accordance with scheme 1, a compound of formula I may be prepared asfollows: Carboxylic acid IV is heated in a suitable solvent, for exampleTHF, with 1,1′-carbonyl-diimidazole before hydrazine-monohydrate wasadded at 0° C. The obtained carboxylic acid hydrazide II was heated witha corresponding acid III-1 in phosphorous oxychloride affording theoxadiazole I-1 which can be further transformed with tin(II) chloride oriron powder in a mixture of ethanol and aqueous HCl at elevatedtemperature to the corresponding phenyl-amines I-2. Amides I-3 can beobtained by stirring phenylamines I-2 with N,N-diisopropylethylamine,DMAP and corresponding carboxylic acid chloride V in a suitable solvent,for example THF, at ambient or elevated temperature or can be obtainedby heating with a corresponding acid, for example formic acid.Amide-alkylation towards I-4 is proceeded by deprotonation of amides I-3with KHMDS in a suitable solvent, for example THF, followed by additionof methyliodide at ambient temperature.

R is as defined as in scheme 1 and the other definitions are asdescribed above.

In accordance with scheme 2, a phenyl-amine I-2 is treated with KHMDSand an appropriate alkyl-bromide, for example cyclopropylmethyliodide,in a suitable solvent, for example THF, to obtain compounds of formulaI-5, I-6 and I-7.

In accordance with scheme 3, benzoimidazolone I-8 is treated with KHMDSand methyliodide in a suitable solvent, for example DMF, at ambienttemperature to obtain compounds of formula I-9 and I-10.

In accordance with scheme 4, phenyl-amine I-11 is treated withcorresponding sulfonyl chloride VI in the presence ofN,N-diisopropylethylamine and DMAP in a suitable solvent, for exampleTHF, at elevated temperature to obtain compounds of formula I-12 andI-13.

R is as described as for scheme 1 and the other definitions are asabove.

In accordance with scheme 5, phenyl fluoride or chloro-pyridine I-14 istreated with a corresponding amine VII in a suitable solvent, forexample DMSO, at elevated temperature to obtain compounds of formulaI-15.

R is as described as for scheme 1 and the other definitions are asabove.

In accordance with scheme 6, thiomorpholine I-16 is treated with acorresponding oxidation agent, for example oxone or potassiummonopersulfate, in a suitable solvent, for example dichloromethane, atelevated temperature to obtain compounds of formula I-17 and I-18.

In accordance with scheme 7, carboxylic acid IV is treated with acorresponding carboxylic acid hydrazide VIII in presence of adehydrating agent, for example 2-chloro-1,3-dimethylimidazoliumchloride, in a suitable solvent, for example dichloromethane, at ambienttemperature to obtain compounds of formula I.

In accordance with scheme 8, indole I-19 is treated with potassiumcarbonate and methyliodide in a suitable solvent, for example DMF, atambient temperature to obtain a compound of formula I-20.

R is as described as for scheme 1 and the other definitions are asabove.

In accordance with scheme 9, carboxylic ester I-21 is hydrolysed understandard conditions and the resulting carboxylic acid is activated witha suitable agent, for example 1, 1′-carbonyl-diimidazole before treatedwith a corresponding amine VII in a suitable solvent, for exampletetrahydrofuran, at elevated temperature to obtain amides of formulaI-22.

In accordance with scheme 10, methyl isoxazole I-23 is halogenated to acompound of formula IX under standard conditions using N-bromosuccinimdeand 2,2′-azobis(2-methylpropionitrile) followed by treatment with (1)water in a suitable solvent, for example DMSO, at elevated temperatureto obtain alcohols of formula I-24; (2) sodium methanolate in a suitablesolvent, for example methanol, at ambient temperature to obtain ethersof formula I-25; or (3) amines, for example methylamine, in presence ofa base, for example potassium carbonate, in a suitable solvent, forexample tetrahydrofuran, at elevated temperature to obtain amines offormula I-26.

In accordance with scheme 11, dichloropyridine I-27 is treated withsodium methanolate in a suitable solvent, for example tetrahydrofuran,at ambient temperature to obtain compounds of formula I-28.

In accordance with scheme 12, 5-chloroisoxazole I-29 is treated withcorresponding amines VII without or with a base, for example potassiumcarbonate, in a suitable solvent, for example DMSO, at ambienttemperature to obtain compounds of formula I-30 and then with sodiumcyanide in a suitable solvent, for example DMF, at ambient temperatureto obtain 5-cyano-isoxazoles of formula I-31.

In accordance with scheme 13, phenyl-iodide I-32 is treated with4,4-difluoropiperidine in the presence oftris(dibenzylideneacetone)di-palladium (0) chloroformcomplex/2-(dicyclohexylphosphino)biphenyl (XI) and sodium tert-butoxideas a base in a suitable solvent, for example toluene, at elevatedtemperature to obtain compounds of formula I-33.

In accordance with scheme 14, bromo-pyridine I-34 is treated with acorresponding amine VII in presence of tetrabutylammonium iodide atelevated temperature to obtain compounds of formula I-35.

As mentioned earlier, the compounds of formula I and theirpharmaceutically usable salts possess valuable pharmacologicalproperties. Compounds of the present invention are ligands for GABA Areceptors containing the α5 subunit and are therefore useful in thetherapy where cognition enhancement is required.

The compounds were investigated in accordance with the test givenhereinafter.

Membrane Preparation and Binding Assay

The affinity of compounds at GABA A receptor subtypes was measured bycompetition for [3H]flumazenil (85 Ci/mmol; Roche) binding to HEK293cells expressing rat (stably transfected) or human (transientlytransfected) receptors of composition

α1β3γ2, α2β3γ2, α3β3γ2 and α5β3γ2.

Cell pellets were suspended in Krebs-tris buffer (4.8 mM KCl, 1.2 mMCaCl₂, 1.2 mM MgCl₂, 120 mM NaCl, 15 mM Tris; pH 7.5; binding assaybuffer), homogenized by polytron for ca. 20 sec on ice and centrifugedfor 60 min at 4° C. (50000 g; Sorvall, rotor: SM24=20000 rpm). The cellpellets were resuspended in Krebs-tris buffer and homogenized bypolytron for ca. 15 sec on ice. Protein was measured (Bradford method,Bio-Rad) and aliquots of 1 mL were prepared and stored at −80° C.

Radioligand binding assays were carried out in a volume of 200 mL(96-well plates) which contained 100 mL of cell membranes,[3H]flumazenil at a concentration of 1 nM for α1, α2, α3 subunits and0.5 nM for α5 subunits and the test compound in the range of10-10⁻³×10⁻⁶ M. Nonspecific binding was defined by 10⁻⁵ M diazepam andtypically represented less than 5% of the total binding. Assays wereincubated to equilibrium for 1 hour at 4° C. and harvested onto GF/Cuni-filters (Packard) by filtration using a Packard harvester andwashing with ice-cold wash buffer (50 mM Tris; pH 7.5). After drying,filter-retained radioactivity was detected by liquid scintillationcounting. Ki values were calculated using Excel-Fit (Microsoft) and arethe means of two determinations.

The compounds of the accompanying examples were tested in the abovedescribed assay, and the preferred compounds were found to possess a Kivalue for displacement of [3H]flumazenil from α5 subunits of the ratGABA A receptor of 400 nM or less. In a preferred embodiment thecompounds of the invention are binding selective for the α5 subunitrelative to the α1, α2 and α3 subunit.

Ki[nM] Example hα5 1 400 2 234 3 391 4 16.4 5 31.1 6 146 7 40.6 8 58.2 9286 10 31.7 11 171 12 106 13 7.5 14 31.0 15 14.8 16 7.7 17 48.8 18 12419 11.6 20 20.5 21 85 22 6.1 23 18.3 24 39.6 25 30.9 26 10.2 27 22.1 283.2 29 6.0 30 226 31 199 32 240 33 7.5 34 7.9 35 31.2 36 134 37 22.9 3819.7 39 16.7 40 179 41 32.5 42 141 43 131 44 88.9 45 100 46 255 47 46.948 38.9 49 39.7 50 250 51 128 52 58.9 53 2.3 54 88.4 55 324 56 2.2 5784.2 58 13.9 59 30.7 60 96.0 61 17.7 62 42.8 63 42.8 64 4.2 65 15.3 6613.4 67 15.5 68 4.2 69 8.1 70 262.2 71 289.1 72 12.0 73 11.9 74 134.3 75128.9 76 189.5 77 2.1 78 42.1 79 234.8 80 468.6 81 86.0 82 3.7 83 162.884 224.8 85 20.6 86 4.8 87 43.8 88 338.8 89 4.6 90 4.8 91 111.6 92 293.093 22.8 94 19.3 95 44.5 96 15.3 97 105.0 98 49.0 99 95.8 100 24.0 10114.5 102 146.3 103 47.6 104 12.1 105 27.1 106 164.8 107 31.1 108 11.3109 2.2 110 19.5 111 4.9 112 31.2 113 7.4 114 6.0 115 131.0 116 4.5 1172.0 118 149.0 119 24.3 120 13.5 121 114.6 122 139.5 123 14.4 124 8.2 12526.8 126 4.5 127 1.7 128 4.2 129 2.5 130 10.5 131 21.2 132 8.6 133 12.8134 5.8 135 9.4 136 15.3 137 24.5 138 31.0 139 16.4 140 23.5 141 17.7142 17.2

The invention also provides pharmaceutical compositions containingcompounds of the invention, for example compounds of formula I and theirpharmaceutically acceptable acid addition salts, and a pharmaceuticallyacceptable carrier. Such pharmaceutical compositions can be in the formof tablets, coated tablets, dragées, hard and soft gelatin capsules,solutions, emulsions or suspensions. The pharmaceutical compositionsalso can be in the form of suppositories or injectable solutions.

The pharmaceutical compounds of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic and organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts etc canbe used as such excipients e.g. for tablets, dragées and hard gelatincapsules. Suitable excipients for soft gelatin capsules are e.g.vegetable oils, waxes, fats, semisolid and liquid polyols etc. Suitableexcipients for the manufacture of solutions and syrups are e.g. water,polyols, saccharose, invert sugar, glucose etc. Suitable excipients forinjection solutions are e.g. water, alcohols, polyols, glycerol,vegetable oils etc. Suitable excipients for suppositories are e.g.natural or hardened oils, waxes, fats, semi-liquid or liquid polyolsetc.

Moreover, the pharmaceutical compositions of the invention can containpreservatives, solubilizers, stabilizers, wetting agents, emulsifiers,sweeteners, colorants, flavorants, salts for varying the osmoticpressure, buffers, masking agents or antioxidants. They can also containstill other therapeutically valuable substances.

Compounds of the invention have high affinity and selectivity for GABA Aα5 receptor binding sites. The invention provides a method for enhancingcognition, which comprises administering to an individual atherapeutically effective amount of a compound of formula I or apharmaceutically acceptable salt thereof. The invention also provides amethod for treating Alzheimer's disease, which comprises administeringto an individual a therapeutically effective amount of a compound offormula I or a pharmaceutically acceptable salt thereof.

The compounds and compositions of the invention can be administered in aconventional manner, for example, orally, rectally, or parenterally. Thecompounds of the invention can be administered orally, for example, inthe form of tablets, coated tablets, dragées, hard and soft gelatincapsules, solutions, emulsions, or suspensions. The compounds of theinvention also can be administered rectally, for example, in the form ofsuppositories, or parenterally, for example, in the form of injectablesolutions.

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, in the case of oraladministration a daily dosage of about 10 to 1000 mg per person of acompound of general formula I should be appropriate, although the aboveupper limit can also be exceeded when necessary.

The following examples illustrate the present invention without limitingit. All temperatures are given in degrees Celsius.

EXAMPLE A

Tablets of the following composition are manufactured in the usualmanner:

mg/tablet Active substance 5 Lactose 45 Corn starch 15 Microcrystallinecellulose 34 Magnesium stearate 1 Tablet weight 100

EXAMPLE B

Capsules of the following composition are manufactured:

mg/capsule Active substance 10 Lactose 155 Corn starch 30 Talc 5 Capsulefill weight 200

The active substance, lactose and corn starch are firstly mixed in amixer and then in a comminuting machine. The mixture is returned to themixer, the talc is added thereto and mixed thoroughly. The mixture isfilled by machine into hard gelatin capsules.

EXAMPLE C

Suppositories of the following composition are manufactured:

mg/supp. Active substance 15 Suppository mass 1285 Total 1300

The suppository mass is melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C.

Thereupon, the finely powdered active substance is added thereto andstirred until it has dispersed completely. The mixture is poured intosuppository moulds of suitable size, left to cool, the suppositories arethen removed from the moulds and packed individually in wax paper ormetal foil.

The following examples 1-142 are provided for illustration of theinvention. They should not be considered as limiting the scope of theinvention, but merely as being representative thereof.

EXAMPLE 1 2-(5-Methyl-3-phenyl-isoxazol-4-yl)-5-phenyl-[1,3,4]oxadiazole

a) 5-Methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide

To a solution of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (5.00 g,24.6 mmol) in THF (50 mL) was added in one portion1,1′-carbonyl-diimidazole (4.39 g, 27.1 mmol). After stirring for 15 minat ambient temperature the solution was warmed to 70° C. and stirred for30 min at this temperature. After the solution was cooled to 0° C.hydrazine monohydrate (2.4 mL, 49.0 mmol) was added over a period of 2min while the temperature raised to 15° C. The resulting suspension wasstirred for 30 min at 0° C. After addition of 20 mL heptane thesuspension was stirred for 15 min at 0° C. and filtered off. Washingwith water and drying afforded the title compound (4.52 g, 85%) as awhite solid. MS: m/e=218.2 [M+H]⁺.

b) 2-(5-Methyl-3-phenyl-isoxazol-4-yl)-5-phenyl-[1,3,4]oxadiazole

To a solution of ethyl benzimidate hydrochloride (376 mg; 2.03 mmol) inethanol (4 mL) was added at 0° C. sodium ethoxide (2.72 M in ethanol,355 L, 0.99 mmol) and stirred for 15 min. The suspension was filteredoff and 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg,0.92 mmol) was added and stirred for 90 h at 70° C. The reaction mixturewas suspended in dioxane (4 mL) and heated in the microwave for 30 minat 180° C. Concentration and then purification by chromatography (SiO₂,heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (163mg, 29%) as a white solid. MS: m/e=304.2 [M+H]⁺.

EXAMPLE 22-(5-Methyl-3-phenyl-isoxazol-4-yl)-5-o-tolyl-[1,3,4]oxadiazole

To a suspension of 5-methyl-3-phenyl-isoxazole-4-carboxylic acidhydrazide (200 mg, 0.92 mmol) in phosphorus oxychloride (1.68 mL, 18.4mmol) was added o-toluic acid (188 mg, 1.38 mmol) and was stirred for 30min at ambient temperature. The suspension was heated for 2 h at 90° C.whereupon it became homogeneous. After cooling to ambient temperature itwas then poured onto a mixture of ethyl acetate (20 mL) and aqueoussodium carbonate (saturated, 20 mL). The aqueous phase was thenseparated and extracted with ethyl acetate (20 mL). The combined organicextracts were then washed with aqueous sodium carbonate and brine.Concentration and trituration in tert-butylmethylether (3 mL) affordedthe title compound (99 mg, 34%) as a white solid. MS: m/e=318.1 [M+H]⁺.

EXAMPLE 32-(3-Methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using 3-methoxybenzoicacid instead of o-toluic acid to the title compound (SiO₂, heptane:ethylacetate=80:20 to 20:80, 205 mg, 67%) which was obtained as a whitesolid. MS: m/e=334.1 [M+H]⁺.

EXAMPLE 42-(2-Methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using 2-methoxybenzoicacid instead of o-toluic acid to the title compound (SiO₂, heptane:ethylacetate 95:5 to 50:50, 170 mg, 55%) which was obtained as a white foam.MS: m/e=334.0 [M+H]⁺.

EXAMPLE 52-(4-Methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using 4-methoxybenzoicacid instead of o-toluic acid to the title compound (SiO₂, heptane:ethylacetate=95:5 to 0:100, 192 mg, 63%) which was obtained as a white foam.MS: m/e=334.2 [M+H]⁺.

EXAMPLE 62-Chloro-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using2-methoxy-nicotinic acid instead of o-toluic acid to the title compound(SiO₂, heptane:ethyl acetate=80:20 to 50:50, 64 mg, 21%) which wasobtained as a white solid. MS: m/e=339.1 [M+H]⁺.

EXAMPLE 78-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-quinoline

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted usingquinoline-8-carboxylic acid instead of o-toluic acid to the titlecompound (SiO₂, heptane:ethyl acetate=80:20 to 50:50, 160 mg, 49%) whichwas obtained as a white solid. MS: m/e=355.2 [M+H]⁺.

EXAMPLE 82-(2-Ethoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using 2-ethoxybenzoicacid instead of o-toluic acid to the title compound (SiO₂, heptane:ethylacetate=80:20 to 50:50, 135 mg, 42%) which was obtained as an off-whitesolid. MS: m/e=348.3 [M+H]⁺.

EXAMPLE 92-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using 2-picolinic acidinstead of o-toluic acid to the title compound (SiO₂, heptane:ethylacetate:dichloromethane=60:20:20 to 0:80:20, 43 mg, 15%) which wasobtained as an off-white solid. MS: m/e 305.2 [M+H]⁺.

EXAMPLE 102-(2,4-Dimethoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using2,4-dimethoxybenzoic acid instead of o-toluic acid to the title compound(SiO₂, heptane:ethyl acetate=80:20 to 50:50, 207 mg, 62%) which wasobtained as a white solid. MS: m/e=364.2 [M+H]⁺.

EXAMPLE 112-(2-Methoxy-4-nitro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (2.00 g, 9.12 mmol) was converted using2-methoxy-4-nitro-benzoic acid instead of o-toluic acid to the titlecompound (2.92 g, 84%) which was obtained as a white solid. MS:m/e=379.2 [M+H]⁺.

EXAMPLE 122-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine

a)2-(5-Methyl-3-phenyl-isoxazol-4-yl)-5-(2-nitro-phenyl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (2.00 g, 9.12 mmol) was converted using 2-nitro-benzoicacid instead of o-toluic acid to the title compound (2.52 g, 79%) whichwas obtained as a light-brown solid. MS: m/e=349.1 [M+H]⁺.

b)2-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine

To a suspension of2-(5-methyl-3-phenyl-isoxazol-4-yl)-5-(2-nitro-phenyl)-[1,3,4]oxadiazole(2.20 g, 63.2 mmol) in ethanol (100 mL) was added under a nitrogenatmosphere aqueous HCl (1 M, 7.6 mL, 76 mmol) and tin(II) chloridedihydrate (7.13 g, 31.6 mmol). The reaction mixture was then stirred for2 h at 90° C., cooled to ambient temperature and poured onto an aqueoussolution of sodium carbonate (saturated, 50 mL) and ethyl acetate (100mL), stirred for 1 h and was filtered over Hyflo®. The Hyflo® was thenwashed with ethyl acetate (500 mL) and the aqueous phase extracted withethyl acetate (100 mL). Drying over sodium sulfate, concentration andpurification by chromatography (SiO₂, heptane:ethyl acetate 95:5 to50:50) afforded the title compound (564 mg, 28%) as a white solid. MS:m/e=319.1 [M+H]⁺.

EXAMPLE 133-Methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine

To a suspension of2-(2-methoxy-4-nitro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.53 mmol) in ethanol (2 mL) was added iron powder (148 mg,2.64 mmol) and aqueous HCl (1 M, 0.53 mL, 0.53 mmol). The reactionmixture was stirred for 2 h at 90° C., cooled to ambient temperature andpoured onto an aqueous solution of sodium carbonate (saturated, 20 mL)and ethyl acetate (20 mL) and then stirred for 1 h. Filtration overHyflo® was followed by washing of the Hyflo® with ethyl acetate. Theaqueous phase was extracted with ethyl acetate (20 mL). Drying oversodium sulfate, concentration and purification by chromatography (SiO₂,heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (80mg, 43%) as a white solid. MS: m/e=349.2 [M+H]⁺.

EXAMPLE 142-(2-Methoxy-4-methyl-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using2-methoxy-4-methyl-benzoic acid instead of o-toluic acid to the titlecompound (SiO₂, heptane:ethyl acetate:dichloromethane=75:5:20 to60:20:20, 155 mg, 48%) which was obtained as a white solid. MS:m/e=348.2 [M+H]⁺.

EXAMPLE 152-(2,5-Dimethoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using2,5-dimethoxybenzoic acid instead of o-toluic acid to the title compound(SiO₂, heptane:ethyl acetate:dichloromethane=75:5:20 to 60:20:20, 176mg, 53%) which was obtained as a white solid. MS: m/e=364.2 [M+H]⁺.

EXAMPLE 16 Cyclopropanecarboxylic acid{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amide

To a solution of3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine(200 mg, 0.57 mmol) in THF (2 mL) was added N,N-diisopropyl ethyl amine(0.15 mL, 0.86 mmol), 4-dimethylaminopyridine (8 mg, 0.06 mmol) andcyclopropanecarbonyl chloride (68 μL, 0.75 mmol). The resultingsuspension was stirred for 18 h at ambient temperature before it wasextracted with a mixture of aqueous sodium carbonate (saturated, 20 mL)and ethyl acetate (20 mL). The aqueous layer was extracted with ethylacetate (20 mL) and the combined organic layers dried over sodiumsulfate. Purification by chromatography (SiO₂, heptane:ethylacetate:dichloromethane=40:40:20 to 10:70:20) afforded the titlecompound (226 mg, 95%) as a light yellow solid. MS: m/e=417.3 [M+H]⁺.

EXAMPLE 17 Cyclopropanecarboxylic acid{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methyl-amide

To a solution of cyclopropanecarboxylic acid{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amide(138 mg, 0.33 mmol) in DMF (2 mL) was added at ambient temperaturepotassium bis(trimethylsilyl)amide (0.91 M in THF, 0.44 mL, 0.40 mmol).After the dark brown solution was stirred for 15 min iodomethane (25 μL,0.40 mmol) was added and the reaction mixture was stirred for 18 h in aclosed flask. It was then extracted with water (20 mL) and ethyl acetate(20 mL). The combined organic layers were then washed with aqueoussodium carbonate (saturated, 20 mL), concentrated, dissolved in ethylacetate (3 mL) and treated with heptane (3 mL). The resulting suspensionwas filtered off and washed with ethyl acetate:heptane 1:1 (3 mL)affording the title compound (83 mg, 58%) as a white solid. MS:m/e=431.3 [M+H]⁺.

EXAMPLE 18(4-{5-[5-(2-Cyclopropyl-ethyl)-3-phenyl-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-3-methoxy-phenyl)-cyclopropylmethyl-amine

To a suspension of3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine(200 mg, 0.57 mmol) in THF (2 mL) was added N,N-diisopropyl ethyl amine(128 μL, 0.75 mmol) and bromomethyl-cyclopropane (61 μL, 0.63 mmol) andthe reaction mixture was stirred for 24 h at ambient temperature. Afteraddition of potassium bis(trimethylsilyl)amide (0.91 M in THF, 0.82 mL,0.75 mmol) stirring was continued for 15 min and furtherbromomethyl-cyclopropane (78 μL, 0.80 mmol) was added. After stirringfor 18 h at ambient temperature further bromomethyl-cyclopropane (0.12mL, 1.2 mmol) was added and stirring continued for 24 h at thistemperature. The reaction mixture was extracted with aqueous sodiumcarbonate (saturated, 20 mL) and ethyl acetate (20 mL). The aqueouslayer was extracted with ethyl acetate (20 mL) and the combined organiclayers dried over sodium sulfate. Concentration and then purification bychromatography (SiO₂, heptane:ethyl acetate:dichloromethane=40:40:20 to0:80:20) afforded the title compound (27 mg, 10%) as a light brownsolid. MS: m/e=457.4 [M+H]⁺.

EXAMPLE 19Cyclopropylmethyl-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amine

To a suspension of3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine(200 mg, 0.57 mmol) in THF was added N,N-diisopropyl ethyl amine (128μL, 0.75 mmol) and bromomethyl-cyclopropane (61 μL, 0.63 mmol) and thereaction mixture was stirred for 24 h at ambient temperature. Afteraddition of potassium bis(trimethylsilyl)amide (0.91 M in THF, 0.82 mL,0.75 mmol) was added stirring was continued for 15 min and furtherbromomethyl-cyclopropane (78 μL, 0.80 mmol) was added. After stirringfor 18 h at ambient temperature further bromomethyl-cyclopropane (0.12mL, 1.2 mmol) was added and stirring continued for 24 h at thistemperature. The reaction mixture was extracted with aqueous sodiumcarbonate (saturated, 20 mL) and ethyl acetate (20 mL). The aqueouslayer was extracted with ethyl acetate (20 mL) and the combined organiclayers dried over sodium sulfate. Concentration and then purification bychromatography (SiO₂, heptane:ethyl acetate:dichloromethane=40:40:20 to0:80:20) afforded the title compound (34 mg, 15%) as a light brownsolid. MS: m/e=403.4 [M+H]⁺.

EXAMPLE 204-{5-[5-(2-Cyclopropyl-ethyl)-3-phenyl-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-3-methoxy-phenylamine

To a suspension of3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine(200 mg, 0.57 mmol) in THF were added N,N-diisopropyl ethyl amine (128μL, 0.75 mmol) and bromomethyl-cyclopropane (61 μL, 0.63 mmol) and thereaction mixture was stirred for 24 h at ambient temperature. Afteraddition of potassium bis(trimethylsilyl)amide (0.91 M in THF, 0.82 mL,0.75 mmol) was added stirring was continued for 15 min and furtherbromomethyl-cyclopropane (78 μL, 0.80 mmol) was added. After stirringfor 18 h at ambient temperature further bromomethyl-cyclopropane (0.12mL, 1.2 mmol) was added and stirring continued for 24 h at thistemperature. The reaction mixture was extracted with aqueous sodiumcarbonate (saturated, 20 mL) and ethyl acetate (20 mL). The aqueouslayer was extracted with ethyl acetate (20 mL) and the combined organiclayers dried over sodium sulfate. Concentration and then purification bychromatography (SiO₂, heptane:ethyl acetate:dichloromethane=40:40:20 to0:80:20) afforded the title compound (28 mg, 12%) as a light brownsolid. MS: m/e=403.4 [M+H]⁺.

EXAMPLE 21N-{3-Methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-bis-methanesulfonyl-amine

To a solution of3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine(200 mg, 0.57 mmol) in THF (2 mL) were added N,N-diisopropyl ethyl amine(0.15 mL, 0.86 mmol), 4-dimethylaminopyridine (8 mg, 0.06 mmol) andmethanesulfonyl chloride (53 μL, 0.69 mmol). The resulting suspensionwas then stirred for 18 h at ambient temperature. FurtherN,N-diisopropyl ethyl amine (0.15 mL, 0.86 mmol) and methanesulfonylchloride (54 μL, 0.689 mmol) was added and stirred was continued for 24h at 50° C. The reaction mixture was extracted with aqueous HCl (1 M, 15mL) and ethyl acetate (20 mL). The aqueous layer was extracted withethyl acetate (20 mL) and the combined organic layers were washed withbrine (half-saturated, 20 mL) and aqueous sodium carbonate (saturated,20 mL). Drying over sodium sulfate and purification by chromatography(SiO₂, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20)afforded the title compound (205 mg, 71%) as a white solid. MS:m/e=505.0 [M+H]⁺.

EXAMPLE 22N-{3-Methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methanesulfonamide

To a solution of3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine(200 mg, 0.57 mmol) in THF (2 mL) was added N,N-diisopropyl ethyl amine(0.15 mL, 0.86 mmol), 4-dimethylaminopyridine (8 mg, 0.06 mmol) andmethanesulfonyl chloride (53 μL, 0.69 mmol). The resulting suspensionwas stirred for 18 h at ambient temperature. Further N,N-diisopropylethyl amine (0.15 mL, 0.86 mmol) and methanesulfonyl chloride (54 μL,0.689 mmol) were added and stirred was continued for 24 h at 50° C. Thereaction mixture was then extracted with aqueous HCl (1 M, 15 mL) andethyl acetate (20 mL). The aqueous layer was extracted with ethylacetate (20 mL) and the combined organic layers were washed with brine(half-saturated, 20 mL) and aqueous sodium carbonate (saturated, 20 mL).Drying over sodium sulfate, concentration and purification bychromatography (SiO₂, heptane:ethyl acetate:dichloromethane=60:20:20 to0:80:20) afforded the title compound (34 mg, 14%) as a light yellowsolid. MS: m/e=427.0 [M+H]⁺.

EXAMPLE 23 Thiophene-3-carboxylicacid-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amide

To a solution of 3-thiophenecarboxylic acid (162 mg, 1.26 mmol) indichloromethane (4 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (242 mg,1.26 mmol). After stirring for 2 min3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine(400 mg, 1.15 mmol) was added and stirring was continued for 3 d atambient temperature. The reaction mixture was extracted with aqueous HCl(1 M, 15 mL) and ethyl acetate (20 mL) and the aqueous layer wasextracted with ethyl acetate (20 mL. Drying over sodium sulfate,concentration and purification by chromatography (SiO₂, heptane:ethylacetate:dichloromethane=60:20:20 to 0:80:20) afforded the title compound(268 mg, 51%) as a white solid. MS: m/e=459.2 [M+H]⁺.

EXAMPLE 242-(4-Fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (2.00 g, 9.12 mmol) was converted using4-fluoro-2-methoxy-benzoic acid instead of o-toluic acid to the titlecompound (SiO₂, heptane:ethyl acetate:dichloromethane=70:10:20 to40:40:20, 1.59 g, 49%) which was obtained as a white solid. MS:m/e=352.3 [M+H]⁺.

EXAMPLE 256-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-benzotriazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using5-carboxy-benzotriazole instead of o-toluic acid to the title compound(SiO₂, heptane:ethyl acetate:dichloromethane=70:20:10 to 20:70:10, 125mg, 39%) which was obtained as a white solid. MS: m/e 345.1 [M+H]⁺.

EXAMPLE 264-{3-Methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine

To a solution of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.57 mmol) in DMSO (2 mL) was added thiomorpholine (0.29 mL,2.85 mmol) and the reaction mixture was stirred for 5 h at 170° C. Aftercooling to ambient temperature it was extracted with water (20 mL) andethyl acetate (20 mL). The aqueous layer was extracted with ethylacetate (20 mL) and the combined organic layers were washed with brine(half-saturated, 20 mL) and aqueous sodium carbonate (saturated, 20 mL).Drying over sodium sulfate and purification by chromatography (SiO₂,heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded thetitle compound (164 mg, 66%) as an off-white solid. MS: m/e=435.3[M+H]⁺.

EXAMPLE 275-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (400 mg, 1.84 mmol) was converted usingbenzimidazole-5-carboxylic acid instead of o-toluic acid to the titlecompound (SiO₂, heptane:ethylacetate:dichloromethane:methanol=70:20:10:0 to 0:80:10:10, 33 mg, 5%)which was obtained as an off-white solid. MS: m/e=344.1 [M+H]⁺.

EXAMPLE 284-{3-Methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine1,1-dioxide

To a solution of4-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine(156 mg, 0.36 mmol) in dichloromethane (2 mL) and methanol (2 mL) wasadded oxone (331 mg, 0.54 mmol) and the reaction mixture was stirred for18 h at ambient temperature and then for 4 h at 50° C. After cooling toambient temperature oxone (331 mg, 0.54 mmol) was added and stirred for18 h at 50° C. before it was cooled to ambient temperature and sodiumbisulfite solution (38%, 1.5 mL) was added and stirred for 15 min. Afterthe addition of aqueous sodium carbonate (saturated, 10 mL) the mixturewas extracted with ethyl acetate (20 mL) and washed with aqueous sodiumcarbonate (20 mL). After drying over sodium sulfate the concentratedresidue was dissolved in dichloromethane (5 mL) and diluted withtert-butylmethylether (20 mL). The dichloromethane was distilled off andthe resulting suspension was filtered affording the title compound (116mg, 69%) as a white solid. MS: m/e=467.2 [M+H]⁺.

EXAMPLE 291-{3-Methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-piperidin-4-ol

As described for example 26,2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.57 mmol) was converted using 4-hydroxy-piperidine instead ofthiomorpholine to the title compound (SiO₂,dichloromethane:methanol=100:0 to 90:10, 197 mg, 79%) which was obtainedas an off-white solid. MS: m/e=433.3 [M+H]⁺.

EXAMPLE 302-(4-Methanesulfonyl-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using4-(methanesulfonyl)-benzoic acid instead of o-toluic acid to the titlecompound (SiO₂, heptane:ethyl acetate:dichloromethane=50:30:20 to20:60:20, 36 mg, 10%) which was obtained as a white solid. MS: m/e=382.1[M+H]⁺.

EXAMPLE 312-(3-Methanesulfonyl-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using3-(methylsulfonyl)-benzoic acid instead of o-toluic acid to the titlecompound (SiO₂, heptane:ethyl acetate:dichloromethane=50:30:20 to20:60:20, 44 mg, 13%) which was obtained as a white solid. MS: m/e=382.1[M+H]⁺.

EXAMPLE 325-(5-Methyl-3-phenyl-isoxazol-4-yl)-2-(4-nitro-phenyl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (2.00 g, 9.21 mmol) was converted using 4-nitro-benzoicacid instead of o-toluic acid to the title compound (1.59 mg, 50%) whichwas obtained as an off-white solid. MS: m/e=349.3 [M+H]⁺.

EXAMPLE 332-(4-Imidazol-1-yl-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 26,2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.57 mmol) was converted using imidazole instead ofthiomorpholine to the title compound (SiO₂, heptane:ethylacetate:dichloromethane=70:10:20 to 40:40:20, 82 mg, 36%) which wasobtained as an off-white solid. MS: m/e=400.2 [M+H]⁺.

EXAMPLE 345-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dihydro-benzoimidazol-2-one

a) 5-(Imidazole-1-carbonyl)-1,3-dihydro-benzoimidazol-2-one

To a solution of 1,1′-carbonyl-diimidazole (11.7 g, 72.3 mmol) in THF(500 mL) was added 3,4-diaminobenzoic acid (5.00 g, 32.9 mmol) andstirred for 3 days at ambient temperature. The reaction mixture wasconcentrated and stirred for 30 min at 80° C. in water (100 mL). Theresulting suspension was then cooled to ambient temperature and themixture was filtered off and washed with water (2×50 mL) to afford thetitle compound (4.94 g, 66%) which was obtained as a white solid. MS:m/e=229.3 [M+H]⁺.

b)5-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dihydro-benzoimidazol-2-one

To a suspension of 5-methyl-3-phenyl-isoxazole-4-carboxylic acidhydrazide (200 mg, 0.92 mmol) in chlorobenzene (2 mL) was added5-(imidazole-1-carbonyl)-1,3-dihydro-benzoimidazol-2-one (315 mg, 1.38mmol) and stirred for 18 h at 100° C. After cooling to ambienttemperature phosphorus oxychloride (126 μL, 1.38 mmol) was added and thesuspension was stirred for 4 h at 100° C. It was then cooled to ambienttemperature and water (2 mL) was added, stirred for 15 min, and theresulting precipitate filtered off and washed with water (5 mL) andtert-butylmethylether (5 mL). Recrystallisation from ethanol affordedthe title compound (257 mg, 78%) which was obtained as a light-greysolid. MS: m/e=360.1 [M+H]⁺.

EXAMPLE 354-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine

As described for example 13,5-(5-methyl-3-phenyl-isoxazol-4-yl)-2-(4-nitro-phenyl)-[1,3,4]oxadiazole(1.49 g, 4.27 mmol) instead of2-(2-methoxy-4-nitro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazolewas converted to the title compound (recrystallisation fromtert-butylmethylether, 580 mg, 43%) which was obtained as a light brownsolid. MS: m/e=319.1 [M+H]⁺.

EXAMPLE 362-(4-Fluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (5.00 g, 23.0 mmol) was converted using 4-fluorobenzoicacid instead of o-toluic acid to the title compound (recrystallisationfrom tert-butylmethylether, 2.98 g, 40%) which was obtained as anoff-white solid. MS: m/e=322.2 [M+H]⁺.

EXAMPLE 374-{4-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine

As described for example 26,2-(4-fluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(400 mg, 1.24 mmol) instead of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazolewas converted to the title compound (SiO₂, heptane:ethylacetate:dichloromethane=70:10:20 to 40:40:20, 309 mg, 61%) which wasobtained as a light brown solid. MS: m/e=405.3 [M+H]⁺.

EXAMPLE 384-{4-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine1,1-dioxide

To a suspension of4-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine(239 mg, 0.59 mmol) in methanol (2 mL) and water (0.5 mL) was addedoxone (545 mg, 0.89 mmol) and stirred for 18 h at 60° C. and for 4 h at50° C. After the reaction mixture was cooled to ambient temperaturefurther oxone (331 mg, 0.54 mmol) was added and stirred for 18 h at 50°C. It was cooled to ambient temperature and aqueous sodium bisulfite(38%, 1.5 mL) was then added and stirred for 15 min. After the additionof aqueous sodium carbonate (saturated, 10 mL) the mixture was extractedwith ethyl acetate (20 mL) and washed with aqueous sodium carbonate(saturated, 20 mL). Drying over sodium sulfate, concentration andpurification by chromatography (SiO₂, heptane:ethylacetate:dichloromethane:methanol=40:50:10:0 to 0:90:0:10) afforded thetitle compound (75 mg, 29%) as a white solid. MS: m/e=437.2 [M+H]⁺.

EXAMPLE 394-{4-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine1-oxide

To a suspension of4-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine(239 mg, 0.59 mmol) in methanol (2 mL) and water (0.5 mL) was addedoxone (545 mg, 0.89 mmol) and stirred for 18 h at 60° C. and for 4 h at50° C. After the reaction mixture was cooled to ambient temperaturefurther oxone (331 mg, 0.54 mmol) was added and stirred for 18 h at 50°C. It was cooled to ambient temperature and aqueous sodium bisulfite(38%, 1.5 mL) was added and stirred for 15 min. After the addition ofaqueous sodium carbonate (saturated, 10 mL) the mixture was extractedwith ethyl acetate (20 mL) and washed with aqueous sodium carbonate(saturated, 20 mL). Drying over sodium sulfate and purification bychromatography (SiO₂, heptane:ethylacetate:dichloromethane:methanol=40:50:10:0 to 0:90:0:10) afforded thetitle compound (50 mg, 20%) as a white solid. MS: m/e=421.1 [M+H]⁺.

EXAMPLE 404-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using isonicotinic acidinstead of o-toluic acid to the title compound (SiO₂, heptane:ethylacetate:dichloromethane:methanol=40:50:10:0 to 0:90:0:10, 57 mg, 20%)which was obtained as a white foam. MS: m/e=305.3 [M+H]⁺.

EXAMPLE 41rac-(2S,6R)-2,6-Dimethyl-4-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine

A suspension of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.62 mmol) in 2,6-dimethylmorpholine (2.00 mL, 16.0 mmol) washeated for 30 min at 200° C. (microwave) followed by stirring undergently reflux for 18 h at 160° C. After addition of DMSO (2 mL) and2,6-dimethylmorpholine (0.50 mL, 4.00 mmol) the solution was stirred foranother 24 h at 160° C. After cooling to ambient temperature thereaction mixture was extracted with water (20 mL) and ethyl acetate (20mL). The aqueous layer was extracted with ethyl acetate (20 mL) and thecombined organic layers were washed with brine (20 mL) and aqueoussodium carbonate (saturated, 20 mL). Drying over sodium sulfate,concentration and purification by chromatography (SiO₂, heptane:ethylacetate:dichloromethane=70:10:20 to 40:40:20) afforded the titlecompound (61 mg, 24%) as a white solid. MS: m/e=417.3 [M+H]⁺.

EXAMPLE 422-(2-Difluoromethoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using2-(difluoromethoxy)-benzoic acid instead of o-toluic acid to the titlecompound (SiO₂, heptane:ethyl acetate:dichloromethane=70:10:20 to40:40:20, 294 mg, 86%) which was obtained as a white solid. MS:m/e=370.0 [M+H]⁺.

EXAMPLE 432-(5-Methyl-3-phenyl-isoxazol-4-yl)-5-(2-trifluoromethoxy-phenyl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using2-(trifluoromethoxy)-benzoic acid instead of o-toluic acid to the titlecompound (SiO₂, heptane:ethyl acetate:dichloromethane=70:10:20 to40:40:20, 134 mg, 38%) which was obtained as a white solid. MS:m/e=388.0 [M+H]⁺.

EXAMPLE 444-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-quinoline

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted usingquinoline-4-carboxylic acid instead of o-toluic acid to the titlecompound (SiO₂, heptane:ethyl acetate:dichloromethane=50:30:20 to20:60:20, 75 mg, 23%) which was obtained as a white solid. MS: m/e=355.2[M+H]⁺.

EXAMPLE 452-(3-Fluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (2.00 g, 9.21 mmol) was converted using 3-fluorobenzoicacid instead of o-toluic acid to the title compound (SiO₂, heptane:ethylacetate:dichloromethane=70:10:20 to 40:40:20, 1.75 mg, 59%) which wasobtained as an off-white solid. MS: m/e 322.1 [M+H]⁺.

EXAMPLE 462-(2-Benzyloxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using2-benzyloxybenzoic acid instead of o-toluic acid to the title compound(SiO₂, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 109mg, 29%) which was obtained as a white solid. MS: m/e=410.1 [M+H]⁺.

EXAMPLE 471-{4-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-piperidine

To a solution of2-(4-fluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.62 mmol) in DMSO (2 mL) was added piperidine (307 μL, 3.11mmol) and the resulting mixture stirred for 5 h at 170° C. After coolingto ambient temperature the reaction mixture was extracted with aqueoushydrochloric acid (1 N, 20 mL) and ethyl acetate (20 mL). The aqueouslayer was extracted with ethyl acetate (20 mL) and the combined organiclayers were washed with brine (half-saturated, 20 mL) and aqueous sodiumcarbonate (saturated, 20 mL). Drying over sodium sulfate andpurification by chromatography (SiO₂, heptane:ethylacetate:dichloromethane=80:0:20 to 50:30:20) afforded the title compound(192 mg, 80%) as a white solid. MS: m/e=387.1 [M+H]⁺.

EXAMPLE 485-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-ylamine

To a suspension of 6-aminonicotinic acid (191 mg, 1.38 mmol) inchlorobenzene (2 mL) was added 1,1′-carbonyl-diimidazole (224 mg, 1.38mmol) and the resulting mixture stirred for 2 h at 90° C. After thesuspension was cooled to ambient temperature5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92mmol) was added and stirred for 1 h at 90° C. After the reaction mixturewas cooled to ambient temperature phosphorous oxychloride (0.84 mL, 9.20mmol) was added and stirring was continued for 4 h at 90° C. The cooledreaction mixture was poured carefully onto a mixture of ethyl acetate(20 mL) and aqueous sodium carbonate (saturated, 20 mL) and was stirredfor 1 h at ambient temperature. The aqueous layer was separated andextracted with ethyl acetate (20 mL) and the combined organic layerswere washed with aqueous sodium carbonate (saturated). Drying oversodium sulfate and purification by chromatography (SiO₂, heptane:ethylacetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5) afforded thetitle compound (27 mg, 9%) as a white solid. MS: m/e=320.0 [M+H]⁺.

EXAMPLE 492-(2-Methoxy-4-trifluoromethyl-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using2-methoxy-4-trifluoromethyl-benzoic acid instead of o-toluic acid to thetitle compound (SiO₂, heptane:ethyl acetate:dichloromethane=70:10:20 to40:40:20, 185 mg, 50%) which was obtained as a white solid. MS:m/e=402.1 [M+H]⁺.

EXAMPLE 502-(5-Methyl-3-phenyl-isoxazol-4-yl)-5-(4-trifluoromethyl-phenyl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using4-trifluoromethyl-benzoic acid instead of o-toluic acid to the titlecompound (SiO₂, heptane:ethyl acetate:dichloromethane=70:10:20 to40:40:20, 114 mg, 33%) which was obtained as a white solid. MS:m/e=372.0 [M+H]⁺.

EXAMPLE 511,3-Dimethyl-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dihydro-benzoimidazol-2-one

5-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dihydro-benzoimidazol-2-one(200 mg, 0.56 mmol) was heated in DMF (2 mL) until the suspension turnedinto solution. After the solution was cooled to ambient temperatureiodomethane (38 μL, 0.61 mmol) was added and stirred for 18 h at thistemperature. The resulting suspension was diluted with DMF (2 mL) andwarmed until the reaction mixture became homogeneous. A solution ofpotassium bis(trimethylsilyl)amide (0.91 M in THF, 673 μL, 0.61 mmol)was added and stirred for 1 h at ambient temperature. Additionaliodomethane (38 μL, 0.61 mmol) was added and stirring was continued foranother 18 h. Additional potassium bis(trimethylsilyl)amide (0.91 M inTHF, 673 μL, 0.61 mmol) was added, stirred for 15 min at ambienttemperature, treated with iodomethane (0.38 μL, 0.61 mmol) and stirredfor 5 h at this temperature. The reaction mixture was diluted with ethylacetate (20 mL) and washed with aqueous sodium carbonate (saturated, 20mL), water (20 mL) and brine (20 mL). The combined aqueous layers wereextracted with ethyl acetate (20 mL) and the combined organic layerswere dried over sodium sulfate. Purification by chromatography (SiO₂,heptane:ethyl acetate:dichloromethane=40:40:20 to 10:70:20) afforded thetitle compound (29 mg, 13%) as a white solid. MS: m/e=388.1 [M+H]⁺.

EXAMPLE 522-(4-Difluoromethoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using4-difluoromethoxy-benzoic acid instead of o-toluic acid to the titlecompound (SiO₂, heptane:ethyl acetate:dichloromethane=70:10:20 to40:40:20, 85 mg, 25%) which was obtained as a white solid. MS: m/e=369.9[M+H]⁺.

EXAMPLE 535-[5-(5-Isopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one

5-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dihydro-benzoimidazol-2-one(200 mg, 0.56 mmol) was heated in DMF (2 mL) until the suspension turnedinto solution. After the solution was cooled to ambient temperatureiodomethane (38 μL, 0.61 mmol) was added and stirred for 18 h at thistemperature. The resulting suspension was diluted with DMF (2 mL) andwarmed until the reaction mixture became homogeneous. A solution ofpotassium bis(trimethylsilyl)amide (0.91 M in THF, 673 μL, 0.61 mmol)was added and stirred for 1 h at ambient temperature. Additionaliodomethane (38 μL, 0.61 mmol) was added and stirring was continued foranother 18 h. Additional potassium bis(trimethylsilyl)amide (0.91 M inTHF, 673 μL, 0.61 mmol) was added, stirred for 15 min at ambienttemperature, treated with iodomethane (0.38 μL, 0.61 mmol) and stirredfor 5 h at this temperature. The reaction mixture was diluted with ethylacetate (20 mL) and washed with aqueous sodium carbonate (saturated, 20mL), water (20 mL) and brine (20 mL). The combined aqueous layers wereextracted with ethyl acetate (20 mL) and the combined organic layerswere dried over sodium sulfate. Purification by chromatography (SiO₂,heptane:ethyl acetate:dichloromethane=40:40:20 to 10:70:20) afforded thetitle compound (38 mg, 16%) as a white solid. MS: m/e=416.1 [M+H]⁺.

EXAMPLE 542-Chloro-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (1.92 mg, 8.83 mmol) was converted using2-chloroisonicotinic acid instead of o-toluic acid to the title compound(SiO₂, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 1.41mg, 47%) which was obtained as a white solid. MS: m/e=339.1 [M+H]⁺.

EXAMPLE 554-{4-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-morpholine

To a solution of2-chloro-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine(200 mg, 0.59 mmol) in DMSO (2 mL) was added morpholine (257 μL, 2.95mmol) and stirred for 18 h under an argon atmosphere at 170° C. Aftercooling to ambient temperature the resulting dark brown solution wasextracted with ethyl acetate (20 mL) and aqueous sodium carbonate(saturated, 20 mL). The aqueous layer was extracted with ethyl acetate(20 mL) and the combined organic layers were washed with water (20 mL)and brine (20 mL). Drying over sodium sulfate and purification bychromatography (SiO₂, heptane:ethyl acetate:dichloromethane=70:10:20 to40:40:20) afforded the title compound (166 mg, 72%) as a white solid.MS: m/e=390.1 [M+H]⁺.

EXAMPLE 564-{3-Methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine1-oxide

To a solution of4-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine(660 mg, 1.52 mmol) in dichloromethane (7 mL), methanol (7 mL) and water(0.1 mL) was added oxone (1.87 g, 3.04 mmol) and stirred for 8 h at 60°C. The reaction mixture was cooled to ambient temperature and aqueoussodium bisulfite (38%, 5 mL) was added and stirred for 1 h. After theaddition of aqueous sodium carbonate (saturated, 30 mL) the mixture wasextracted with dichloromethane (30 mL) and washed with aqueous sodiumcarbonate (half-saturated, 30 mL). Drying over sodium sulfate andpurification by chromatography (SiO₂, heptane:ethylacetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5) afforded thetitle compound (102 mg, 15%) as an off-white solid. MS: m/e=451.1[M+H]⁺.

EXAMPLE 574-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-benzonitrile

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (1.09 mg, 5.00 mmol) was converted using 4-cyanobenzoicacid instead of o-toluic acid to the title compound (SiO₂, heptane:ethylacetate=100:0 to 50:50, 490 mg, 30%) which was obtained as a whitesolid. MS: m/e=329.1 [M+H]⁺.

EXAMPLE 582-[2-Methoxy-4-(2-methyl-imidazol-1-yl)-phenyl]-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 26,2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(190 mg, 0.54 mmol) was converted using 2-methyl-imidazole instead ofthiomorpholine to the title compound (SiO₂, heptane:ethylacetate:dichloromethane:methanol=20:70:10:0 to 0:90:0:10, 27 mg, 12%)which was obtained a light-brown solid. MS: m/e=414.1 [M+H]⁺.

EXAMPLE 592-[4-(2-Methyl-imidazol-1-yl)-phenyl]-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 47,2-(4-fluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.62 mmol) was converted using 2-methyl-imidazole instead ofpiperidine to the title compound (110 mg, 46%) which was obtained alight-brown waxy solid. MS: m/e=384.0 [M+H]⁺.

EXAMPLE 602-(5-Ethyl-3-phenyl-isoxazol-4-yl)-5-(4-fluoro-2-methoxy-phenyl)-[1,3,4]oxadiazole

To a solution of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(1.00 g, 2.85 mmol) in DMF (10 mL) was added potassiumhexamethyldisilazane (0.91 M in tetrahydrofuran, 3.44 mL, 3.13 mmol) atambient temperature and the resulting mixture was stirred for 1 h. Afteraddition of iodomethane (0.20 mL, 3.13 mmol) the reaction mixture wasstirred for 20 h at this temperature. Further potassiumhexamethyldisilazane (0.91 M in tetrahydrofuran, 3.44 mL, 3.13 mmol) andiodomethane (0.20 mL, 3.13 mmol) were added and stirring was continuedfor another 1.5 h. The reaction mixture was poured onto aqueous ammoniumchloride (saturated, 50 mL) and was extracted with ethyl acetate. Dryingover sodium sulfate and purification by chromatography (SiO₂,heptane:ethyl acetate:dichloromethane=70:10:20 to 0:80:20) afforded thetitle compound (14 mg, 1%) as a white solid. MS: m/e=366.1 [M+H]⁺.

EXAMPLE 612-(4-Fluoro-2-methoxy-phenyl)-5-(5-isopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

To a solution of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(1.00 g, 2.85 mmol) in DMF (10 mL) was added potassiumhexamethyldisilazane (0.91 M in tetrahydrofuran, 3.44 mL, 3.13 mmol) atambient temperature and the resulting mixture was stirred for 1 h. Afteraddition of iodomethane (0.20 mL, 3.13 mmol) the reaction mixture wasstirred for 20 h at this temperature. Further potassiumhexamethyldisilazane (0.91 M in tetrahydrofuran, 3.44 mL, 3.13 mmol) andiodomethane (0.20 mL, 3.13 mmol) were added and stirring was continuedfor another 1.5 h. The reaction mixture was poured onto aqueous ammoniumchloride (saturated, 50 mL) and was extracted with ethyl acetate. Dryingover sodium sulfate and purification by chromatography (SiO₂,heptane:ethyl acetate:dichloromethane=70:10:20 to 0:80:20) afforded thetitle compound (146 mg, 14%) as a white solid. MS: m/e=380.1 [M+H]⁺.

EXAMPLE 62 Thiophene-2-sulfonic acid{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amide

To a solution of3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine(200 mg, 0.57 mmol) in tetrahydrofuran (5 mL) were addedN,N-diisopropylamine (111 mg, 0.86 mmol), 4-dimethylaminopyridine (7.0mg, 0.06 mmol) and thiophenesulfonyl chloride (126 mg, 0.69 mmol) andthe reaction mixture was stirred at ambient temperature for 4 d. Theresulting suspension was extracted with ethyl acetate (20 mL) and thecombined organic layers were washed with aqueous sodium carbonate(saturated). Drying over sodium sulfate and purification bychromatography (SiO₂, heptane:ethyl acetate:dichloromethane=50:30:20 to20:60:20) afforded the title compound (95 mg, 33%) as an orange solid.MS: m/e=495.1 [M+H]⁺.

EXAMPLE 63 Propane-2-sulfonic acid{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amide

To a solution of3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine(200 mg, 0.57 mmol) in tetrahydrofuran (5 mL) was added at 0° C.potassium bis(trimethylsilyl)amide (0.91 M in tetrahydrofuran, 1.51 mL,1.38 mmol). After stirring for 15 min at this temperatureisopropylsulfonyl chloride (319 mg, 2.24 mmol) was added and stirringwas continued at ambient temperature for 76 h. Further isopropylsulfonylchloride (107 mg, 0.75 mmol) and pyridine (454 mg, 5.74) were added andstirring was continued for 24 h. The resulting suspension was extractedwith ethyl acetate (20 mL) and the combined organic layers were washedwith aqueous sodium carbonate (saturated). Drying over sodium sulfateand purification by chromatography (SiO₂, heptane:ethylacetate:dichloromethane 50:30:20 to 20:60:20) afforded the titlecompound (29 mg, 11%) as a yellow solid. MS: m/e 455.2 [M+H]⁺.

EXAMPLE 64{3-Methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-(tetrahydro-pyran-4-yl)-amine

As described for example 26,2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.57 mmol) was converted using 4-aminotetrahydropyran (173 mg,1.71 mmol) and N,N-diisopropylethylamine (147 mg, 1.14 mmol) instead ofthiomorpholine to the title compound (SiO₂, heptane:ethylacetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5, 73 mg, 30%)which was obtained as a white solid. MS: m/e=433.3 [M+H]⁺.

EXAMPLE 65{3-Methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-(1-methyl-piperidin-4-yl)-amine

As described for example 26,2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.57 mmol) was converted using 1-methylpiperidin-4-amine (195mg, 1.71 mmol) and N,N-diisopropylethylamine (147 mg, 1.14 mmol) insteadof thiomorpholine to the title compound (SiO₂, heptane:ethylacetate:dichloromethane:methanol 40:40:20:0 to 0:75:20:5, 56 mg, 22%)which was obtained as an off-white solid. MS: m/e=446.2 [M+H]⁺.

EXAMPLE 661-{3-Methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-piperazine

As described for example 26,2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.57 mmol) was converted using piperazine instead ofthiomorpholine to the title compound (SiO₂,dichloromethane:(dichloromethane:methanol:ammonia=70:27:3)=92:2 to50:50, 40 mg, 17%) which was obtained as an off-white solid. MS:m/e=418.3 [M+H]⁺.

EXAMPLE 671-{3-Methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-4-methyl-piperazine

As described for example 26,2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.57 mmol) was converted using 1-methylpiperazine instead ofthiomorpholine to the title compound (SiO₂,dichloromethane:(dichloromethane:methanol:ammonia=70:27:3)=92:2 to80:20, 117 mg, 48%) which was obtained as an off-white solid. MS:m/e=432.4 [M+H]⁺.

EXAMPLE 684-{3-Methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine

As described for example 26,2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.57 mmol) was converted using morpholine instead ofthiomorpholine to the title compound (SiO₂, heptane:ethylacetate:dichloromethane=60:20:20 to 0:80:20, 132 mg, 55%) which wasobtained as an off-white solid. MS: m/e=419.2 [M+H]⁺.

EXAMPLE 692-(5-Cyclopropyl-3-phenyl-isoxazol-4-yl)-5-(2-methoxy-phenyl)-[1,3,4]oxadiazole

a) 5-Cyclopropyl-3-phenyl-isoxazole-4-carboxylic acid ethyl ester

To a solution of N-hydroxybenzenecarboximidoyl chloride (TetrahedronLetters, 47(9), 1457-1460, 2006, 500 mg, 3.21 mmol) andcyclopropyl-propynoic acid ethyl ester (Organic Syntheses, 66, 173-179,1988, 515 mg, 3.21 mmol) in diethyl ether (5 mL) was added dropwise overa period of 2 min at ambient temperature triethylamine (0.54 ml, 3.86mmol) and the reaction mixture was stirred for 3 d at this temperature.The resulting suspension was diluted with tert-butylmethylether (5 mL)and water (10 mL). The aqueous layer was extracted withtert-butylmethylether (10 ml) and the organic layers were washed withwater (10 mL) and brine (10 mL). Drying over sodium sulfate andpurification by chromatography (SiO₂, heptane:ethyl acetate=98:2 to80:20) afforded the title compound (414 mg, 50%) as a colorless liquid.MS: m/e=258.1 [M+H]⁺.

b) 5-Cyclopropyl-3-phenyl-isoxazole-4-carboxylic acid

To a solution of 5-cyclopropyl-3-phenyl-isoxazole-4-carboxylic acidethyl ester (408 mg, 1.58 mmol) in ethanol (4 mL) was added aqueoussodium hydroxide (1 N, 3.17 mL, 3.17 mmol) and the mixture was stirredfor 3 h at 80° C. The ethanol was distilled off and the residue dilutedwith water (5 mL) and acified with aqueous HCl (IN) to pH=1. Theresulting suspension was filtered off and washed with water affordingthe title compound (314 mg, 86%) as a white solid. MS: m/e=230.3[M+H]⁺.

c)2-(5-Cyclopropyl-3-phenyl-isoxazol-4-yl)-5-(2-methoxy-phenyl)-[1,3,4]oxadiazole

To a suspension of 5-cyclopropyl-3-phenyl-isoxazole-4-carboxylic acid(236 mg, 1.03 mmol) in dichloromethane (2 mL) were added2-methoxybenzhydrazide (205 mg, 1.24 mmol),2-chloro-1,3-dimethylimidazolium chloride (383 mg, 2.26 mmol) andtriethylamine (0.52 ml, 5.15 mmol) at ambient temperature. The resultingsuspension was stirred for 18 h at this temperature before diluting withdichloromethane (20 ml) and washing with water (20 mL) and brine (20mL). The aqueous layers were extracted with dichlormethane and thecombined organic layers dried over sodium sulfate. Purification bychromatography (SiO₂, heptane:ethyl acetate:dichloromethane=70:10:20 to40:40:20) afforded the title compound (121 mg, 33%) as a white solid.MS: m/e=360.2 [M+H]⁺.

EXAMPLE 702-Cyclohexyl-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted usingcyclohexanecarboxylic acid instead of o-toluic acid to the titlecompound (SiO₂, heptane:ethyl acetate:dichloromethane=70:10:20 to40:40:20, 233 mg, 82%) which was obtained as a white solid. MS: m/e362.3 [M+H]⁺.

EXAMPLE 714-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-benzoicacid methyl ester

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (2.00 g, 9.21 mmol) was converted using mono-methylterephthalate instead of o-toluic acid to the title compound (1.98 mg,60%) which was obtained as a colorless liquid. MS: m/e=310.3 [M+H]⁺.

EXAMPLE 72{3-Methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-dimethyl-amine

As described for example 26,2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.57 mmol) was converted using dimethylamine hydrochloride (232mg, 2.85 mmol) and N,N-diisopropylethylamine (294 mg, 2.28 mmol) insteadof thiomorpholine to the title compound (SiO₂, heptane:ethylacetate:dichloromethane 70:10:20 to 40:40:20, 8 mg, 4%) which wasobtained as a light brown solid. MS: m/e=377.3 [M+H]⁺.

EXAMPLE 732-(5-Cyclopropyl-3-phenyl-isoxazol-4-yl)-5-(4-fluoro-2-methoxy-phenyl)-[1,3,4]oxadiazole

a) 5-Cyclopropyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide

As described for example 1a,5-cyclopropyl-3-phenyl-isoxazole-4-carboxylic acid (5.69 g, 24.8 mmol)instead of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid was convertedto the title compound (6.13 mg, 99%) which was obtained as a whitesolid. MS: m/e=244.3 [M+H]⁺.

b)2-(5-Cyclopropyl-3-phenyl-isoxazol-4-yl)-5-(4-fluoro-2-methoxy-phenyl)-[1,3,4]oxadiazole

As described for example 2,5-cyclopropyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (1.32 g,5.43 mmol) was converted using 4-fluoro-2-methoxy-benzoic acid insteadof o-toluic acid to the title compound (SiO₂, heptane:ethylacetate:dichloromethane=70:10:20 to 40:40:20, 631 mg, 31%) which wasobtained as a white solid. MS: m/e=319.0 [M+H]⁺.

EXAMPLE 745-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-indole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (500 mg, 2.30 mmol) was converted usingindole-5-carboxylic acid instead of o-toluic acid to the title compound(SiO₂, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 430mg, 55%) which was obtained as a colorless liquid. MS: m/e=343.1 [M+H]⁺.

EXAMPLE 751-Methyl-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-indole

To a solution of5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-indole(150 mg, 0.44 mmol) in DMF (2 mL) was added potassium carbonate (121 mg,0.88 mmol) and iodomethane (0.04 ml, 0.66 mmol) and the reaction mixturewas stirred for 3 d in a closed round bottomed flask at ambienttemperature. The mixture was extracted with water (20 ml) and ethylacetate (20 mL). The aqueous layer was extracted with ethyl acetate andthe combined organic layers were washed with aqueous sodium carbonate(half saturated, 20 mL) and brine (20 mL). Drying over sodium sulfateand purification by chromatography (SiO₂, heptane:ethylacetate:dichloromethane=70:10:20 to 40:40:20) afforded the titlecompound (136 mg, 87%) as a white solid. MS: m/e=357.2 [M+H]⁺.

EXAMPLE 762-(2,4-Difluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using2,4-difluorobenzoic acid instead of o-toluic acid to the title compound(SiO₂, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 199mg, 64%) which was obtained as a white solid. MS: m/e=340.2 [M+H]⁺.

EXAMPLE 774-{4-[5-(5-Cyclopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine

As described for example 26,2-(4-fluoro-2-methoxy-phenyl)-5-(5-cyclopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.53 mmol) instead of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazolewas converted using morpholine instead of thiomorpholine to the titlecompound (SiO₂, heptane:ethyl acetate:dichloromethane=60:20:20 to0:80:20, 138 mg, 59%) which was obtained as a white solid. MS: m/e=445.3[M+H]⁺.

EXAMPLE 78N-Cyclopropyl-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-benzamide

a) 4-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-benzoicacid

To a solution of4-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-benzoicacid methyl ester (1.95 g, 5.47 mmol) in methanol (10 mL) was addedaqueous sodium hydroxide (1 M, 11 mL, 11 mmol) and the mixture wasstirred for 3 h at 70° C. After concentration the residue was dilutedwith water (20 mL) and the resulting suspension was acidified withaqueous HCl (1 N) to pH=1. filtration and washing with water affordedthe title compound (1.90 g, 99%) which was obtained as a white solid.MS: m/e=348.1 [M+H]⁺.

b)Imidazol-1-yl-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methanone

To a suspension of4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-benzoicacid (1.90 g, 5.48 mmol) in tetrahydrofuran (20 mL) was added1,1′-carbonyl-diimidazole (978 mg, 6.03 mmol) and the mixture wasstirred for 0.5 h at 80° C. After cooling to ambient temperature theresulting suspension was poured onto water (100 mL), stirred for 15 minat ambient temperature and was filtered. Washing with water and dryingafforded the title compound (1.51 g, 69%) which was obtained as a yellowsolid. MS: m/e=398.2 [M+H]⁺.

c)N-Cyclopropyl-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-benzamide

To a suspension ofimidazol-1-yl-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methanone(200 mg, 0.50 mmol) in tetrahydrofuran (2 mL) was added cyclopropylamine(37 mg, 0.65 mmol) and the mixture was stirred for 3 h at 80° C. Aftercooling to ambient temperature the resulting suspension wasconcentrated. Purification by chromatography (SiO₂, heptane:ethylacetate:dichloromethane=60:20:20 to 0:80:20) afforded the title compound(149 mg, 77%) as a white solid. MS: m/e=387.2 [M+H]⁺.

EXAMPLE 79N-Cyclopropylmethyl-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-benzamide

As described for example 78c,imidazol-1-yl-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methanone(200 mg, 0.50 mmol) was converted using aminomethylcyclopropane insteadof cyclopropylamine to the title compound (SiO₂, heptane:ethylacetate:dichloromethane=60:20:20 to 0:80:20, 88 mg, 44%) which wasobtained as a white solid. MS: m/e=433.3 [M+H]⁺.

EXAMPLE 80{4-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholin-4-yl-methanone

As described for example 78c,imidazol-1-yl-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methanone(200 mg, 0.50 mmol) was converted using morpholine instead ofcyclopropylamine to the title compound (SiO₂, heptane:ethylacetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5, 196 mg, 94%)which was obtained as a colorless foam. MS: m/e=417.3 [M+H]⁺.

EXAMPLE 814-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-N-(tetrahydro-pyran-4-yl)-benzamide

As described for example 78c,imidazol-1-yl-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methanone(200 mg, 0.50 mmol) was converted using 4-aminotetrahydropyran insteadof cyclopropylamine to the title compound (SiO₂, heptane:ethylacetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5, 100 mg, 46%)which was obtained a white solid. MS: m/e=431.3 [M+H]⁺.

EXAMPLE 82{4-[5-(5-Cyclopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-(tetrahydro-pyran-4-yl)-amine

As described for example 26,2-(4-fluoro-2-methoxy-phenyl)-5-(5-cyclopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.53 mmol) instead of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazolewas converted using 4-aminotetrahydropyran (161 mg, 1.59 mmol) andN,N-diisopropylethylamine (137 mg, 1.06 mmol) instead of thiomorpholineto the title compound (SiO₂, heptane:ethylacetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5, 84 mg, 35%)which was obtained as a white solid. MS: m/e=459.4 [M+H]⁺.

EXAMPLE 832-(2,5-Difluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using2,5-difluorobenzoic acid instead of o-toluic acid to the title compound(SiO₂, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 211mg, 68%) which was obtained as a white solid. MS: m/e=340.2 [M+H]⁺.

EXAMPLE 842-(2,3-Difluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using2,3-difluorobenzoic acid instead of o-toluic acid to the title compound(SiO₂, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 108mg, 35%) which was obtained as a white solid. MS: m/e=340.2 [M+H]⁺.

EXAMPLE 852-(2-Methoxy-4-[1,2,3]triazol-2-yl-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 26,2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.57 mmol) was converted using 1H-1,2,3-triazole (197 mg, 2.84mmol) and potassium carbonate (47 mg, 0.34 mmol) instead ofthiomorpholine to the title compound (SiO₂, heptane:ethylacetate:dichloromethane=70:10:20 to 20:60:20, 34 mg, 15%) which wasobtained as a white solid. MS: m/e=401.2 [M+H]⁺.

EXAMPLE 862-(2-Methoxy-4-[1,2,3]triazol-1-yl-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 26,2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.57 mmol) was converted using 1H-1,2,3-triazole (197 mg, 2.84mmol) and potassium carbonate (47 mg, 0.34 mmol) instead ofthiomorpholine to the title compound (SiO₂, heptane:ethylacetate:dichloromethane=70:10:20 to 20:60:20, 56 mg, 25%) which wasobtained as a white solid. MS: m/e 401.2 [M+H]⁺.

EXAMPLE 872-(4,5-Difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using4,5-difluoro-2-methoxybenzoic acid instead of o-toluic acid to the titlecompound (SiO₂, heptane:ethyl acetate:dichloromethane=70:10:20 to0:80:20, 168 mg, 49%) which was obtained as a white solid. MS: m/e=340.2[M+H]⁺.

EXAMPLE 88{4-[5-(4-Fluoro-2-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-3-phenyl-isoxazol-5-ylmethyl}-methyl-amine

To a solution of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(241 mg, 0.69 mmol) in carbon tetrachloride (2 mL) was addedN-bromosuccinimide (122 mg, 0.69 mmol) and2,2′-azobis(2-methylpropionitrile) (11 mg, 0.07 mmol) and the reactionmixture was stirred for 18 h at 70° C. It was diluted withdichloromethane (10 mL) and washed with aqueous sodium hydrogencarbonate(1 N, 10 mL). The aqueous phase was extracted with dichloromethane anddried over sodium sulfate. The resulting crude material was suspended inmethylamine solution (2 M in THF, 2.0 mL, 4.0 mmol) and potassiumcarbonate (110 mg, 0.80 mmol) was added. The reaction mixture wasstirred for 2 h at 50° C. The mixture was diluted with ethyl acetate (20ml), washed twice aqueous sodium carbonate (half saturated) and wasextracted with ethyl acetate. Drying over sodium sulfate andpurification by chromatography (SiO₂, heptane:ethylacetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5) afforded thetitle compound (119 mg, 46%) as a white solid. MS: m/e=381.2 [M+H]⁺.

EXAMPLE 89N-{3-Methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-acetamide

To a solution of3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine(200 mg, 0.57 mmol) in tetrahydrofuran (4 mL) were addedN,N-diisopropylamine (111 mg, 0.86 mmol), 4-dimethylaminopyridine (7.0mg, 0.06 mmol) and acetyl chloride (59 mg, 0.75 mmol) and the reactionmixture was stirred at ambient temperature for 6 h. The resultingsuspension was extracted with ethyl acetate (20 mL) and the combinedorganic layers were washed with aqueous sodium carbonate (saturated).Drying over sodium sulfate and concentration afforded the title compound(162 mg, 72%) as a yellow solid. MS: m/e=391.2 [M+H]⁺.

EXAMPLE 90N-{3-Methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-propionamide

To a solution of3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine(200 mg, 0.57 mmol) in tetrahydrofuran (4 mL) were addedN,N-diisopropylamine (111 mg, 0.86 mmol), 4-dimethylaminopyridine (7.0mg, 0.06 mmol) and propionyl chloride (69 mg, 0.75 mmol) and thereaction mixture was stirred at ambient temperature for 22 h. Afterheating at 50° C. for another 26 h the resulting suspension wasextracted with ethyl acetate (20 mL) and the combined organic layerswere washed with aqueous sodium carbonate (saturated). Drying oversodium sulfate and concentration afforded the title compound (206 mg,89%) as a yellow solid. MS: m/e=405.3 [M+H]⁺.

EXAMPLE 912-(4-Fluoro-2-methoxy-phenyl)-5-(5-methoxymethyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

To a solution of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(1.95 g, 5.56 mmol) in carbon tetrachloride (20 ml) was added N-bromosuccinimide (990 mg, 5.56 mmol) and 2,2′-azobis(2-methylpropionitrile)(46 mg, 0.28 mmol) and the reaction mixture was stirred for 4 h at 70°C. Further 2,2′-azobis(2-methylpropionitrile) (46 mg, 0.28 mmol) wasadded and stirring was continued for another 14 h at 70° C. N-Bromosuccinimide (378 mg, 2.12 mmol) was added and the mixture stirred foranother 4 h at 90° C. After the reaction mixture was cooled to 0° C. thesuspension was filtered off and was washed with dichloromethane (30 mL)and aqueous sodium hydrogencarbonate (1 N). It was extracted withdichloroemthane and dried over sodium sulfate resulting in crudematerial (1.66 g). A part of this light brown solid (200 mg) wasdissolved in tetrahydropyran (2 mL), sodium methoxide (30% in methanol,0.43 ml, 2.32 mmol) was added and the resulting mixture was stirred for1 h at ambient temperature. It was diluted with ethyl acetate (20 mL)and washed aqueous ammonium chloride (saturated). The aqueous layerswere extracted with ethyl acetate and the combined organic layers weredried over sodium sulfate. Purification by chromatography (SiO₂,heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded thetitle compound (25 mg, 14%) as a white solid. MS: m/e=382.3 [M+H]⁺.

EXAMPLE 92{4-[5-(4-Fluoro-2-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-3-phenyl-isoxazol-5-yl}-methanol

To a solution of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(1.95 g, 5.56 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (990 mg, 5.56 mmol) and 2,2′-azobis(2-methylpropionitrile)(46 mg, 0.28 mmol) and the reaction mixture was stirred for 4 h at 70°C. Further 2,2′-azobis(2-methylpropionitrile) (46 mg, 0.28 mmol) wasadded and stirring was continued for another 14 h at 70° C. N-Bromosuccinimide (378 mg, 2.12 mmol) was added and the mixture stirred foranother 4 h at 90° C. After the reaction mixture was cooled to 0° C. thesuspension was filtered off and was washed with dichloromethane (30mL 1) and aqueous sodium hydrogencarbonate (1 N). It was extracted withdichloroemthane and dried over sodium sulfate resulting in crudematerial (1.66 g). A part of this light brown solid (200 mg) wassuspended in water (0.5 mL) and DMSO (2.0 mL) and the reaction mixturewas stirred for 18 h at 60° C. the resulting solution was diluted withethyl acetate (10 mL) and washed with water (10 mL) and brine (10 mL).The aqueous layers were extracted with ethyl acetate. Drying over sodiumsulfate and urification by chromatography (SiO₂, heptane:ethylacetate:dichloromethane=70:10:20 to 20:60:20) afforded the titlecompound (57 mg, 33%) as a white solid. MS: m/e=368.1 [M+H]⁺.

EXAMPLE 932-Methoxy-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using2-methoxynicotinic acid instead of o-toluic acid to the title compound(SiO₂, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20, 163mg, 53%) which was obtained as a white solid. MS: m/e=335.3 [M+H]⁺.

EXAMPLE 944-(4-{5-[3-(3-Chloro-phenyl)-5-methyl-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-3-methoxy-phenyl)-morpholine

To a solution of 3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylicacid (200 mg, 0.85 mmol) in dichloromethane (4 mL) was added2-methoxy-4-morpholin-4-yl-benzoic acid hydrazide (266 mg, 0.85 mmol)and 2-chloro-1,3-dimethylimidazolium chloride (313 mg, 1.85 mmol). Afterthe solution was stirred for 15 min at ambient temperature triethylamine(0.59 ml, 4.21 mmol) was added over a period of 2 min and the reactionmixture was stirred for 18 h at this temperature. It was diluted withethyl acetate (20 mL 1) and washed with aqueous sodium carbonate (halfsaturated). The aqueous layers were extracted with ethyl acetate. Dryingover sodium sulfate and purification by chromatography (SiO₂,heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20) afforded thetitle compound (235 mg, 62%) as a white solid. MS: m/e=453.1 [M+H]⁺.

EXAMPLE 954-{3-Methoxy-4-[5-(3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine

As described for example 94, 3-phenyl-isoxazole-4-carboxylic acid(Polish Journal of Chemistry, 56(2), 257-266, 1982, 200 mg, 1.06 mmol)instead of 3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid wasconverted to the title compound (SiO₂, heptane:ethylacetate:dichloromethane 60:20:20 to 0:80:20, 29 mg, 8%) which wasobtained as a white solid. MS: m/e=405.3 [M+H]⁺.

EXAMPLE 964-{4-[5-(3,5-Diphenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine

As described for example 94, 3,5-diphenyl-isoxazole-4-carboxylic acid(Heterocycles, 29(4), 667-677, 1989, 200 mg, 0.75 mmol) instead of3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid was convertedto the title compound (SiO₂, heptane:ethylacetate:dichloromethane=60:20:20 to 0:80:20, 168 mg, 46%) which wasobtained as a white solid. MS: m/e=481.2 [M+H]⁺.

EXAMPLE 974-(4-{5-[3-(2-Chloro-phenyl)-5-methyl-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-3-methoxy-phenyl)-morpholine

As described for example 94,3-(2-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid (200 mg, 0.84mmol) instead of 3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylicacid was converted to the title compound (SiO₂, heptane:ethylacetate:dichloromethane=60:20:20 to 0:80:20, 227 mg, 60%) which wasobtained as an off-white solid. MS: m/e=453.1 [M+H]⁺.

EXAMPLE 984-(4-{5-[3-(4-Fluoro-phenyl)-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-3-methoxy-phenyl)-morpholine

As described for example 94, 3-(4-fluoro-phenyl)-isoxazole-4-carboxylicacid (WO2001029015, 200 mg, 0.90 mmol) instead of3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid was convertedto the title compound (SiO₂, heptane:ethylacetate:dichloromethane=60:20:20 to 0:80:20, 33 mg, 9%) which wasobtained as an off-white solid. MS: m/e=423.1 [M+H]⁺.

EXAMPLE 992-Chloro-6-methoxy-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine

a)2,6-Dichloro-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (400 mg, 1.84 mmol) was converted using2,6-dichloronicotinic acid instead of o-toluic acid to the titlecompound (SiO₂, heptane:ethyl acetate=80:20 to 40:60, 240 mg, 35%) whichwas obtained as a white solid. MS: m/e=373.0/375.0 [M+H]⁺.

a)2-Chloro-6-methoxy-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine

To a solution of2,6-dichloro-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine(316 mg, 0.85 mmol) in tetrahydrofuran (3 mL) and methanol (3 mL) wasadded sodium hydride (55% dispersion in mineral oil, 41 mg, 0.93 mmol)and the reaction mixture was stirred for 4 h at ambient temperature. Theresulting suspension was diluted with dichloromethane (10 mL) and waswashed brine (half saturated, 10 mL). The aqueous layers were extractedwith dichloromethane (10 mL) and dried over sodium sulfate. The filtratewas treated with tert-butylmethylether (20 mL) and the dichloromethanewas distilled off. The resulting suspension was stirred for 5 min,filtered off and washed with tert-butylmethylether affording the titlecompound (51 mg, 16%) which was obtained as a white solid. MS: m/e=369.0[M+H]⁺.

EXAMPLE 1002,6-Dimethoxy-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (500 mg, 2.30 mmol) was converted using2,6-dimethoxynicotinic acid instead of o-toluic acid to the titlecompound (SiO₂, heptane:ethyl acetate=80:20 to 40:60, 204 mg, 24%) whichwas obtained as a white solid. MS: m/e=365.2 [M+H]⁺.

EXAMPLE 1014-(4-{5-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-3-methoxy-phenyl)-morpholine

As described for example 94,3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid (132 mg, 0.60mmol) instead of 3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylicacid was converted to the title compound (SiO₂, heptane:ethylacetate:dichloromethane=60:20:20 to 0:80:20, 120 mg, 46%) which wasobtained as a white solid. MS: m/e=437.2 [M+H]⁺.

EXAMPLE 1024-{3-Methoxy-4-[5-(5-methyl-3-pyridin-3-yl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine

As described for example 94,3-pyridin-3-yl-5-methyl-isoxazole-4-carboxylic acid (122 mg, 0.60 mmol)instead of 3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid wasconverted to the title compound (SiO₂, heptane:ethylacetate:dichloromethane:methanol=40:50:10:0 to 0:90:0:10, 147 mg, 59%)which was obtained as a white solid. MS: m/e=420.1 [M+H]⁺.

EXAMPLE 1034-(3-Methoxy-4-{5-[5-methyl-3-(4-trifluoromethyl-phenyl)-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-phenyl)-morpholine

a) 3-(4-Trifluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid

As described for example 69b,3-(4-trifluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester(Journal of Agricultural and Food Chemistry, 43(1), 219-228, 1995, 329mg, 1.10 mmol) instead of 5-cyclopropyl-3-phenyl-isoxazole-4-carboxylicacid ethyl ester was converted to the title compound (239 mg, 80%) whichwas obtained as a white solid. MS: m/e=270.4 [M−H]⁻.

b)4-(3-Methoxy-4-{5-[5-methyl-3-(4-trifluoromethyl-phenyl)-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-phenyl)-morpholine

As described for example 94,3-(4-trifluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid (162 mg,0.60 mmol) instead of3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid was convertedto the title compound (SiO₂, heptane:ethylacetate:dichloromethane=60:20:20 to 0:80:20, 202 mg, 70%) which wasobtained as a white solid. MS: m/e=487.3 [M+H]⁺.

EXAMPLE 1044-(3-Methoxy-4-{5-[5-methyl-3-(4-methyl-phenyl)-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-phenyl)-morpholine

As described for example 94,3-(4-methyl-phenyl)-5-methyl-isoxazole-4-carboxylic acid (Journal of theChemical Society, 5838-5845, 1963, 130 mg, 0.60 mmol) instead of3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid was convertedto the title compound (SiO₂, heptane:ethylacetate:dichloromethane:methanol=40:50:10:0 to 0:90:0:10, 67 mg, 26%)which was obtained as a white solid. MS: m/e=433.3 [M+H]⁺.

EXAMPLE 1054-{4-[5-(5-Chloro-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine

As described for example 94, 5-chloro-3-phenyl-isoxazole-4-carboxylicacid (Journal of Organic Chemistry, 51(6), 945-947, 1986, 610 mg, 2.73mmol) instead of 3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylicacid was converted to the title compound (SiO₂, heptane:ethylacetate=60:40 to 0:100, 582 mg, 49%) which was obtained as a light brownsolid. MS: m/e=439.1 [M+H]⁺.

EXAMPLE 106{4-[5-(2-Methoxy-4-morpholin-4-yl-phenyl)-[1,3,4]oxadiazol-2-yl]-3-phenyl-isoxazol-5-yl}-dimethyl-amine

To a suspension of4-{4-[5-(5-chloro-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine(100 mg, 0.23 mmol) in DMSO (1 mL) was added dimethylamine hydrochloride(93 mg, 1.14 mmol) and potassium carbonate (158 mg, 1.14 mmol). Thereaction mixture was stirred for 2 h at ambient temperature. It wasdiluted with water (5 mL) and the resulting suspension was stirred for15 min at this temperature. Filtration and washing with water (5 mL) andtert-buitylmethylether (5 mL) afforded the title compound (80 mg, 78%)which was obtained as an off-white solid. MS: m/e=448.2 [M+H]⁺.

EXAMPLE 1074-{4-[5-(2-Methoxy-4-morpholin-4-yl-phenyl)-[1,3,4]oxadiazol-2-yl]-3-phenyl-isoxazol-5-yl}-morpholine

As described for example 106,4-{4-[5-(5-chloro-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine(100 mg, 0.23 mmol) using morpholine instead of dimethylaminehydrochloride and potassium carbonate was converted to the titlecompound (100 mg, 90%) which was obtained as an off-white solid. MS:m/e=490.3 [M+H]⁺.

EXAMPLE 1084-(4-{5-[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-3-methoxy-phenyl)-morpholine

As described for example 94,3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid (Journal of theChemical Society, 5838-5845, 1963, 94 mg, 0.43 mmol) instead of3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid was convertedto the title compound (92 mg, 50%) which was obtained as a white solid.MS: m/e=437.2 [M+H]⁺.

EXAMPLE 1094-(4-{5-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-yl]-[1,3,4]oxadiazol-2-yl}-3-methoxy-phenyl)-morpholine

As described for example 94,3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid (23 mg, 0.10mmol) instead of 3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylicacid was converted to the title compound (SiO₂, heptane:ethyl acetate80:20 to 20:80, 24 mg, 55%) which was obtained as a white solid. MS:m/e=453.1 [M+H]⁺.

EXAMPLE 1104-{3-Methoxy-4-[5-(5-methyl-3-thiophen-2-yl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine

As described for example 94,5-methyl-3-thiophen-2-yl-isoxazole-4-carboxylic acid (Journal of theChemical Society, 5838-5845, 1963, 200 mg, 0.96 mmol) instead of3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid was convertedto the title compound (SiO₂, heptane:ethyl acetate=80:20 to 20:80, 157mg, 39%) which was obtained as an off-white solid. MS: m/e=425.2 [M+H]⁺.

EXAMPLE 111Ethyl-{4-[5-(2-methoxy-4-morpholin-4-yl-phenyl)-[1,3,4]oxadiazol-2-yl]-3-phenyl-isoxazol-5-yl}-amine

As described for example 106,4-{4-[5-(5-chloro-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine(100 mg, 0.23 mmol) using ethylamine instead of dimethylaminehydrochloride and potassium carbonate was converted to the titlecompound (88 mg, 86%) which was obtained as a white solid. MS: m/e=448.3[M+H]⁺.

EXAMPLE 1124,4-Difluoro-1-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-piperidine

a)2-(4-Iodo-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (1.00 g, 4.60 mmol) was converted using 4-iodobenzoicacid instead of o-toluic acid to the title compound (SiO₂, heptane:ethylacetate:dichloromethane=70:10:20 to 40:40:20, 1.21 g, 62%) which wasobtained as a white solid. MS: m/e=430.2 [M+H]⁺.

b)4,4-Difluoro-1-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-piperidine

To a solution of2-(4-iodo-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.47 mmol) in toluene (2 mL) were added under an atmosphere ofnitrogen 2-(dicyclohexylphosphino)biphenyl (15 mg, 0.04 mmol),tris(dibenzylideneacetone)di-palladium(0) chloroform complex (15 mg,0.01 mmol), sodium tert-butoxide (107 mg, 1.12 mmol) and4,4-difluoropiperidine hydrochloride (88 mg, 0.56 mmol). The reactionmixture was stirred for 1 h at 100° C. and was extracted with water (20mL) and ethyl acetate (20 mL). The aqueous layer was extracted withethyl acetate and the combined organic layers were washed with brine.Drying over sodium sulfate and purification by chromatography (SiO₂,heptane:ethyl acetate=80:20 to 50:50) afforded the title compound (138mg, 70%) as a light yellow solid. MS: m/e=423.3 [M+H]⁺.

EXAMPLE 1134-{3-Methoxy-4-[5-(3-phenyl-5-pyrazol-1-yl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine

As described for example 106,4-{4-[5-(5-chloro-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine(100 mg, 0.23 mmol) using pyrazole instead of dimethylaminehydrochloride was converted to the title compound (85 mg, 79%) which wasobtained as an off-white solid. MS: m/e 471.3 [M+H]⁺.

EXAMPLE 1144-{2-Fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine

As described for example 26,2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(153 mg, 0.41 mmol) instead of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazolewas converted using morpholine instead of thiomorpholine to the titlecompound (SiO₂, heptane:ethyl acetate:methanol=60:40:0 to 0:95:5, 20 mg,11%) which was obtained as an off-white solid. MS: m/e=437.0 [M+H]⁺.

EXAMPLE 1154-[5-(2-Methoxy-4-morpholin-4-yl-phenyl)-[1,3,4]oxadiazol-2-yl]-3-phenyl-isoxazole-5-carbonitrile

To a suspension of4-{4-[5-(5-chloro-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine(145 mg, 0.33 mmol) in DMF (2 mL) was added sodium cyanide (18 mg, 0.36mmol) and the mixture was stirred for 18 h at ambient temperature. Theresulting yellow-green suspension was treated with water (15 ml) andcooled to 0° C. After stirring for 15 min at 0° C. the suspension wasfiltered off and washed twice with ice cold water (5 ml) affording thetitle compound (119 mg, 84%) which was obtained as a yellow solid. MS:m/e=430.3 [M+H]⁺.

EXAMPLE 1164-{2-Fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine

As described for example 26,2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(400 mg, 1.08 mmol) instead of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazolewas converted to the title compound (460 mg, 94%) which was obtained asan off-white solid. MS: m/e=453.2 [M+H]⁺.

EXAMPLE 1174-{2-Fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine1,1-dioxide

To a suspension of4-{2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine(400 mg, 0.88 mmol) in methanol (6 mL) and water (0.3 mL) was addedpotassium monopersulfate triple salt (1.09 g, 1.77 mmol) under anatmosphere of nitrogen and the mixture was heated for 18 h at 80° C. Thereaction mixture was cooled to ambient temperature, sodium bisulfite(38% in water, 3 mL) was added and stirred for 0.5 h at ambienttemperature. The resulting suspension was extracted with dichloromethane(20 mL) and washed with aqueous sodium carbonate (half saturated).Drying over sodium sulfate and purification by chromatography (SiO₂,heptane:ethyl acetate:dichloromethane=40:40:20 to 10:70:20) afforded thetitle compound (228 mg, 53%) as a white solid. MS: m/e=485.3 [M+H]⁺.

EXAMPLE 1182-(5-Methyl-3-phenyl-isoxazol-4-yl)-5-(2,4,5-trifluoro-phenyl)-[1,3,4]oxadiazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (4.18 g, 19.2 mmol) was converted using2,4,5-trifluorobenzoic acid instead of o-toluic acid to the titlecompound (3.16 g, 46%) which was obtained as a white solid. MS:m/e=358.1 [M+H]⁺.

EXAMPLE 1194-{2,5-Difluoro-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine

As described for example 26,2-(2,4,5-trifluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(400 mg, 1.12 mmol) instead of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazolewas converted to the title compound (348 mg, 71%) which was obtained asan off-white solid. MS: m/e=441.2 [M+H]⁺.

EXAMPLE 1204-{2,5-Difluoro-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine1,1-dioxide

As described for example 117,4-{2,5-difluoro-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine(208 mg, 0.47 mmol) instead of4-{2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholinewas converted to the title compound (SiO₂, heptane:ethylacetate:dichloromethane=40:40:20 to 10:70:20, 129 mg, 58%) which wasobtained as an off-white solid. MS: m/e=473.3 [M+H]⁺.

EXAMPLE 1212-(5-Methyl-3-phenyl-isoxazol-4-yl)-5-thiophen-2-yl-[1,3,4]oxadiazole

To a suspension of 5-methyl-3-phenylisoxazole-4-carboxylic acid (357 mg,1.76 mmol) in dichloromethane (7 mL) was added thiophene-2-carboxylicacid hydrazide (250 mg, 1.76 mmol) and 2-chloro-1,3-dimethylimidazoliumchloride (654 mg, 3.87 mmol). After the solution was stirred for 15 minat ambient temperature triethylamine (1.2 mL, 8.79 mmol) was added at 0°C. and the light brown suspension was stirred for 18 h while warming toambient temperature. It was washed with water (25 mL) and aqueous sodiumcarbonate (half saturated, 25 mL). The aqueous layers were extractedwith dichloromethane and the combined organic layers were dried oversodium sulfate. Purification by chromatography (SiO₂, heptane:ethylacetate=100:0 to 70:30) afforded the title compound (233 mg, 43%) as alight yellow semisolid. MS: m/e=310.3 [M+H]⁺.

EXAMPLE 1222-(5-Methyl-3-phenyl-isoxazol-4-yl)-5-thiophen-3-yl-[1,3,4]oxadiazole

As described for example 121, 5-methyl-3-phenylisoxazole-4-carboxylicacid (357 mg, 1.76 mmol) using thiophene-3-carboxylic acid hydrazideinstead of thiophene-2-carboxylic acid hydrazide was converted to thetitle compound (SiO₂, heptane:ethyl acetate=90:10 to 60:40, 207 mg, 38%)which was obtained as a yellow semisolid. MS: m/e=310.3 [M+H]⁺.

EXAMPLE 1234-{3-Methoxy-4-[5-(5-methyl-3-thiophen-3-yl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine

a) 5-Methyl-3-thiophen-3-yl-isoxazole-4-carboxylic acid ethyl ester

As described for example 69a, N-hydroxy-thiophene-3-carboximidoylchloride (Organic Letters, 8(17), 3679-3680, 2006, 11.4 g, 69.6 mmol)instead of N-hydroxybenzenecarboximidoyl chloride using ethyl2-butynoate instead of cyclopropyl-propynoic acid ethyl ester wasconverted to the title compound (15.0 g, 91%) which was obtained as adark brown liquid. MS: m/e=238.0 [M+H]⁺.

b) 5-Methyl-3-thiophen-3-yl-isoxazole-4-carboxylic acid

As described for example 69b,5-methyl-3-thiophen-3-yl-isoxazole-4-carboxylic acid ethyl ester (2.73g, 11.5 mmol) instead of 5-cyclopropyl-3-phenyl-isoxazole-4-carboxylicacid ethyl ester was converted to the title compound (1.60 g, 67%) whichwas obtained as a brown solid. MS: m/e=210.1 [M+H]⁺.

c)4-{3-Methoxy-4-[5-(5-methyl-3-thiophen-3-yl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-morpholine

As described for example 94,5-methyl-3-thiophen-3-yl-isoxazole-4-carboxylic acid (200 mg, 0.96 mmol)instead of 3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid wasconverted to the title compound (SiO₂, ethylacetate:dichloromethane=10:90 to 30:70, 35 mg, 10%) which was obtainedas an off-white solid. MS: m/e=378.2 [M+H]⁺.

EXAMPLE 124(2-Methoxy-ethyl)-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-amine

As described for example 26,2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.57 mmol) was converted using 2-methoxyethylamine instead ofthiomorpholine to the title compound (SiO₂, heptane:ethyl acetate=50:50to 0:100, 78 mg, 34%) which was obtained as an off-white foam. MS:m/e=407.4 [M+H]⁺.

EXAMPLE 1254-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazole

As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (200 mg, 0.92 mmol) was converted using1H-benzoimidazole-4-carboxylic acid instead of o-toluic acid to thetitle compound (SiO₂, dichloromethane:methanol:ammonia=95:5:0)=100:0 to80:20, 32 mg, 10%) which was obtained as a white solid. MS: m/e=344.2[M+H]⁺.

EXAMPLE 126{2-Fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-(2-methylsulfanyl-ethyl)-amine

As described for example 26,2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(300 mg, 0.81 mmol) instead of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazolewas converted using 2-(methylthio)ethylamine instead of thiomorpholineto the title compound (273 mg, 76%) which was obtained as an off-whitesolid. MS: m/e 441.2 [M+H]⁺.

EXAMPLE 127{2-Fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-(2-methanesulfonyl-ethyl)-amine

As described for example 117,{2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-(2-methylsulfanyl-ethyl)-amine(200 mg, 0.45 mmol) instead of4-{2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholinewas converted to the title compound (SiO₂, heptane:ethylacetate:methanol=50:50:0 to 0:95:5, 140 mg, 65%) which was obtained asan off-white solid. MS: m/e=473.1 [M+H]⁺.

EXAMPLE 1281-(2-{2-Fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamino}-ethyl)-pyrrolidin-2-one

As described for example 26,2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.54 mmol) instead of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazolewas converted using 1-(2-amino-ethyl)-pyrrolidin-2-one instead ofthiomorpholine to the title compound (231 mg, 89%) which was obtained asan off-white solid. MS: m/e=478.2 [M+H]⁺.

EXAMPLE 1292-{2-Fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamino}-ethanol

As described for example 26,2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.54 mmol) instead of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazolewas converted using ethanolamine instead of thiomorpholine to the titlecompound (160 mg, 72%) which was obtained as an off-white solid. MS:m/e=411.2 [M+H]⁺.

EXAMPLE 130rac-{2-Fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-(tetrahydro-furan-2-ylmethyl)-amine

As described for example 26,2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.54 mmol) instead of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazolewas converted using rac-tetrahydrofurfurylamine instead ofthiomorpholine to the title compound (129 mg, 53%) which was obtained asan off-white solid. MS: m/e=451.2 [M+H]⁺.

EXAMPLE 131{2-Fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-pyridin-2-ylmethyl-amine

As described for example 26,2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.54 mmol) instead of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazolewas converted using 2-(aminoethyl)pyridine instead of thiomorpholine tothe title compound (188 mg, 76%) which was obtained as an off-whitesolid. MS: m/e=458.3 [M+H]⁺.

EXAMPLE 132{2-Fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-(2-pyrrolidin-1-yl-ethyl)-amine

As described for example 26,2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.54 mmol) instead of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazolewas converted using 1-(2-aminoethyl)pyrrolidine instead ofthiomorpholine to the title compound (145 mg, 58%) which was obtained asan off-white solid. MS: m/e=464.2 [M+H]⁺.

EXAMPLE 1331-(2-{2-Fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamino}-ethyl)-imidazolidin-2-one

As described for example 26,2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.54 mmol) instead of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazolewas converted using 1-(2-aminoethyl)imidazolidin-2-one instead ofthiomorpholine to the title compound (203 mg, 78%) which was obtained asan off-white solid. MS: m/e 479.2 [M+H]⁺.

EXAMPLE 134N-{3-Methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-formamide

A mixture of3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine(200 mg, 0.57 mmol) and formic acid (2.1 mL, 55.6 mmol) was stirred at90° C. for 2 h. After concentration purification of the residue bychromatography (SiO₂, heptane:ethyl acetate:methanol=50:50:0 to 0:95:5)afforded the title compound (21 mg, 10%) as a yellow solid. MS:m/e=377.3 [M+H]⁺.

EXAMPLE 135N′-{2-Fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-N,N-dimethyl-ethane-1,2-diamine

As described for example 26,2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole(200 mg, 0.54 mmol) instead of2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazolewas converted using N,N-dimethylethylenediamine instead ofthiomorpholine to the title compound (202 mg, 85%) which was obtained asan off-white solid. MS: m/e=438.4 [M+H]⁺.

EXAMPLE 1364-{5-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-morpholine

a)2-Chloro-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine

To a solution of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide(5.00 g, 23.0 mmol) in dichloromethane (100 mL) was added6-chloronicotinic acid (4.71 g, 29.9 mmol) and2-chloro-1,3-dimethylimidazolium chloride (8.56 g, 50.6 mmol). After thesuspension was stirred for 15 min at ambient temperature, it was cooledto 0° C. and N,N-diisopropyl ethyl amine (19.7 mL, 115 mmol) was addedslowly. The reaction mixture was stirred for 18 h while warming toambient temperature. It was washed with aqueous sodium carbonate(saturated) and the aqueous layers were extracted with dichloromethane.Drying over sodium sulfate and purification by chromatography (SiO₂,heptane:ethyl acetate=80:20 to 50:50) afforded the title compound (4.78g, 61%) as a light yellow solid. MS: m/e=339.2 [M+H]⁺.

b)4-{5-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-morpholine

To a solution of2-chloro-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine(200 mg, 0.59 mmol) in DMSO (2 mL) was added morpholine (257 mg, 2.95mmol) and the reaction mixture was heated for 1 h at 160° C. Aftercooling to ambient temperature it was diluted with ethyl acetate (20 mL)and washed with aqueous sodium carbonate (saturated) and water. Dryingover sodium sulfate and purification by chromatography (SiO₂,heptane:ethyl acetate=80:20 to 70:30) afforded the title compound (162g, 70%) as a white solid. MS: m/e=390.3 [M+H]⁺.

EXAMPLE 1372-{5-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-ylamino}-ethanol

As described for example 136b,2-chloro-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine(200 mg, 0.59 mmol) was converted using ethanolamine instead ofmorpholine to the title compound (126 mg, 59%) which was obtained as anoff-white solid. MS: m/e=364.3 [M+H]⁺.

EXAMPLE 1384-{5-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-thiomorpholine

As described for example 136b,2-chloro-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine(400 mg, 1.18 mmol) was converted using thiomorpholine instead ofmorpholine to the title compound (126 mg, 59%) which was obtained as anoff-white solid. MS: m/e=406.3 [M+H]⁺.

EXAMPLE 139{5-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-(tetrahydro-pyran-4-yl)-amine

As described for example 136b,2-chloro-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine(200 mg, 0.59 mmol) was converted using 4-aminotetrahydropyran insteadof morpholine to the title compound (117 mg, 49%) which was obtained asa light yellow solid. MS: m/e=404.4 [M+H]⁺.

EXAMPLE 1405′-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol

As described for example 136b,2-chloro-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine(200 mg, 0.59 mmol) was converted using 4-hydroxypiperidine instead ofmorpholine to the title compound (17 mg, 7%) which was obtained as alight yellow solid. MS: m/e=404.5 [M+H]⁺.

EXAMPLE 1414-{5-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-thiomorpholine1,1-dioxide

As described for example 117,4-{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-thiomorpholine(200 mg, 0.49 mmol) instead of4-{2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholinewas converted to the title compound (SiO₂, heptane:ethyl acetate=50:50to 0:100, 157 mg, 73%) which was obtained as a white solid. MS:m/e=438.1 [M+H]⁺.

EXAMPLE 1424-{6-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-3-yl}-morpholine

a)5-Bromo-2-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine

As described for example 137a, 5-methyl-3-phenyl-isoxazole-4-carboxylicacid hydrazide (4.14 g, 19.0 mmol) using 5-bromo-2-carboxy pyridineinstead of 6-chloronicotinic acid was converted to the title compound(2.83 g, 39%) which was obtained as a brown solid. MS: m/e=385.1 [M+H]⁺.

b)4-{6-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-3-yl}-morpholine

A mixture of5-bromo-2-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine(200 mg, 0.52 mmol), morpholine (455 μL, 5.22 mmol) andtetrabutylammonium iodide (41 mg, 0.10 mmol) was irradiated in themicrowave for 1.5 h at 160° C. After cooling to ambient temperature theresulting suspension was diluted with ethyl acetate (15 mL) and stirredfor 15 min at this temperature. Filtering off and washing with water (2mL) and with ethyl acetate (1 mL) afforded the title compound (95 mg,47%) which was obtained as a light brown solid. MS: m/e=390.3 [M+H]⁺.

1. A compound of formula I

wherein R¹ is hydrogen, halogen, aryl, heterocyclyl, heteroaryl, cyano,lower alkyl, —(CH₂)_(n)-cycloalkyl, —(CH₂)_(n)—N(R)₂, —(CH₂)_(n)—O-loweralkyl or —(CH₂)_(n)—OH; n is 0, 1 or 2 R is hydrogen or lower alkyl; R²is heteroaryl selected from the group consisting of quinolyl, indolyl,pyridinyl, triazolyl, benzotriazolyl, isoxazolyl, thiophenyl,benzoimidazolyl, dihydrobenzimidazolyl-2-one, imidazolyl, oxazolyl,oxadiazolyl and pyrazinyl or is heterocyclyl, each of which isoptionally substituted by one or more substituents, selected from thegroup consisting of halogen, cyano, nitro, lower alkyl, lower alkoxy,lower alkoxy substituted by halogen, lower alkyl substituted by halogen,C(O)O-lower alkyl, lower alkylsulfonyl, —NR^(a)R^(b), —C(O)—NR^(a)R^(b),—C(O)-heterocyclyl, benzyloxy, heterocyclyl optionally substituted byhydroxy, halogen or lower alkyl, or is heteroaryl optionally substitutedby lower alkyl; R^(a) and R^(b) are independently hydrogen, loweralkylsulfonyl, —C(O)H, —(CH₂)_(n)—N(R)₂, —(CH₂)_(n)—O-lower alkyl,—(CH₂)_(n)—S-lower alkyl, —(CH₂)_(n)—S(O)₂-lower alkyl,heteroarylsulfonyl, lower alkyl, —(CH₂)_(n)-heterocyclyl, optionallysubstituted by lower alkyl, or is —(CH₂)_(n)-cycloalkyl,—(CH₂)_(n)-heteroaryl, —(CH₂)_(n)—OH, —(CO)—R′, wherein R′ is loweralkyl, cycloalkyl or heteroaryl; R³ is aryl or heteroaryl, which areoptionally substituted by halogen or lower alkyl substituted by halogen;or a pharmaceutically acceptable acid addition salt thereof.
 2. Thecompound of claim 1, wherein R² is heteroaryl selected from the groupconsisting of quinolyl, indolyl, pyridinyl, triazolyl, benzotriazolyl,isoxazolyl, thiophenyl, benzoimidazolyl, dihydrobenzimidazolyl-2-one,imidazolyl, oxazolyl, oxadiazolyl and pyrazinyl, which is optionallysubstituted by one or more substituent, selected from the groupconsisting of halogen, cyano, nitro, lower alkyl, lower alkoxy, loweralkoxy substituted by halogen, lower alkyl substituted by halogen,C(O)O-lower alkyl, lower alkylsulfonyl, —NR^(a)R^(b), —C(O)—NR^(a)R^(b),—C(O)-heterocyclyl, benzyloxy, and heterocyclyl optionally substitutedby hydroxy, halogen or lower alkyl, or is heteroaryl optionallysubstituted by lower alkyl.
 3. The compound of claim 2, selected fromthe group consisting of2-chloro-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,8-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-quinoline,2-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazole,5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dihydro-benzoimidazol-2-one,4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-quinoline,5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-ylamine,and1,3-dimethyl-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dihydro-benzoimidazol-2-one.4. The compound of claim 2, selected from the group consisting of5-[5-(5-isopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one,2-chloro-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,4-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-morpholine,5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-indole,2-methoxy-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,2-chloro-6-methoxy-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,2,6-dimethoxy-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,2-(5-Methyl-3-phenyl-isoxazol-4-yl)-5-thiophen-2-yl-[1,3,4]oxadiazole,and2-(5-methyl-3-phenyl-isoxazol-4-yl)-5-thiophen-3-yl-[1,3,4]oxadiazole.5. The compound of claim 2, selected from the group consisting of4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazole,4-{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-morpholine,2-{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-ylamino}ethanol,4-{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-thiomorpholine,{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-(tetrahydro-pyran-4-yl)-amine,5′-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol,4-{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}thiomorpholine1,1-dioxide and4-{6-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-3-yl}-morpholine.6. The compound of claim 1, wherein R² is heterocyclyl, which isoptionally substituted by one or more substituents, selected from thegroup consisting of halogen, cyano, nitro, lower alkyl, lower alkoxy,lower alkoxy substituted by halogen, lower alkyl substituted by halogen,C(O)O-lower alkyl, lower alkylsulfonyl, —NR^(a)R^(b), —C(O)—NR^(a)R^(b),—C(O)-heterocyclyl, benzyloxy, and heterocyclyl optionally substitutedby hydroxy, halogen or lower alkyl, or is heteroaryl optionallysubstituted by lower alkyl.
 7. The compound of claim 1, wherein R² ispyridinyl optionally substituted by halogen, lower alkoxy, heterocyclylor NR^(a)R^(b).
 8. The compound of claim 7, selected from the groupconsisting of2-chloro-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,2-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-ylamine,2-chloro-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,4-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-morpholine,2-methoxy-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,and2-chloro-6-methoxy-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine.9. The compound of claim 7, selected from the group consisting of2,6-dimethoxy-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine,4-{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-morpholine,[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-ylamino}-ethanol,4-{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-thiomorpholine,{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-(tetrahydro-pyran-4-yl)-amine,5′-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol,4-{5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-2-yl}-thiomorpholine1,1-dioxide and4-{6-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridin-3-yl}-morpholine.10. The compound of claim 1, wherein R² is quinolinyl.
 11. The compoundof claim 10, selected from the group consisting of8-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-quinolineand4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-quinoline.12. The compound of claim 1, wherein R² is 1-H-benzoimidazol-5-yl,1,3-dihydro-benzolimidazol-2-on-5-yl or1,3-dimethyl-1,3-dihydro-benzoimidazol-2-on-5-yl.
 13. The compound claim12, selected from the group consisting of5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazole,5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dihydro-benzoimidazol-2-one,1,3-dimethyl-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dihydro-benzoimidazol-2-oneand5-[5-(5-isopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one.14. A pharmaceutical composition comprising a compound of formula I

wherein R¹ is hydrogen, halogen, aryl, heterocyclyl, heteroaryl, cyano,lower alkyl, —(CH₂)_(n)-cycloalkyl, —(CH₂)_(n)—N(R)₂, —(CH₂)_(n)—O-loweralkyl or —(CH₂)_(n)—OH; n is 0, 1 or 2 R is hydrogen or lower alkyl; R²is heteroaryl selected from the group consisting of quinolyl, indolyl,pyridinyl, triazolyl, benzotriazolyl, isoxazolyl, thiophenyl,benzoimidazolyl, dihydrobenzimidazolyl-2-one, imidazolyl, oxazolyl,oxadiazolyl and pyrazinyl or is heterocyclyl, each of which isoptionally substituted by one or more substituents, selected from thegroup consisting of halogen, cyano, nitro, lower alkyl, lower alkoxy,lower alkoxy substituted by halogen, lower alkyl substituted by halogen,C(O)O-lower alkyl, lower alkylsulfonyl, —NR^(a)R^(b), —C(O)—NR^(a)R^(b),—C(O)-heterocyclyl, benzyloxy, heterocyclyl optionally substituted byhydroxy, halogen or lower alkyl, or is heteroaryl optionally substitutedby lower alkyl; R^(a) and R^(b) are independently hydrogen, loweralkylsulfonyl, —C(O)H, —(CH₂)_(n)—N(R)₂, —(CH₂)_(n)—O-lower alkyl,—(CH₂)_(n)—S-lower alkyl, —(CH₂)_(n)—S(O)₂-lower alkyl,heteroarylsulfonyl, lower alkyl, —(CH₂)_(n)-heterocyclyl, optionallysubstituted by lower alkyl, or is —(CH₂)_(n)-cycloalkyl,—(CH₂)_(n)-heteroaryl, —(CH₂)_(n)—OH, —(CO)—R′, wherein R′ is loweralkyl, cycloalkyl or heteroaryl; R³ is aryl or heteroaryl, which areoptionally substituted by halogen or lower alkyl substituted by halogen;or a pharmaceutically acceptable acid addition salt thereof and apharmaceutically acceptable carrier.